Heterocyclic compound

ABSTRACT

wherein each symbol is as defined in the Description, or a salt thereof has a superior RBP4-lowering action, and is useful as a medicament for the prophylaxis or treatment of a disease or symptom mediated by an increase in RBP4 or retinol supplied by RBP4.

TECHNICAL FIELD

The present invention relates to a heterocyclic compound useful as amedicament for the prophylaxis or treatment of a disease or conditionmediated by an increase in RBP4 or retinol supplied by RBP4 such asage-related macular degeneration, Stargardt's disease and the like.

BACKGROUND OF THE INVENTION

It is known that retinol binding protein 4 (hereinafter sometimes to beabbreviated as “RBP4”) is a sole blood retinol transfer protein mainlyproduced in the liver.

RBP4 forms a complex by binding to retinol and TTR (transthyretin) andis stably present in blood. When RBP4 is dissociated from TTR andbecomes free, it is decomposed in and excreted from the kidneycomparatively rapidly. It is unknown whether the binding of RBP4 andretinol is indeed essential for the formation of a complex with TTR.However, fenretinide, a retinol derivative, inhibits binding of RBP4 andretinol, and consequently inhibits formation of a complex with TTR. Itis known that administration of fenretinide to an animal induceslowering of blood RBP4 (non-patent document 1).

The relationship between retinol supplied by RBP4 and ophthalmicdiseases has been reported. For example, an excessive vitamin A level inthe eye can induce various retina diseases including maculardegeneration, and a decrease in RBP4 is effective for the prophylaxis ortreatment of these ophthalmic diseases (patent document 1).

Fenretinide has been investigated in patients affected with geographicatrophy (GA), which is the most progressed form of atrophic age-relatedmacular degeneration (AMD). Fenretinide has been suggested todiscontinue accumulation of retinol (vitamin A) toxin via affinity toRBP4. It is assumed to delay formation and accumulation of toxicityby-products, for example, A2E (bis-retinoid pyridinium) considered to beinvolved in the loss of eyesight in diseases such as GA and the like.Sirion Therapeutics, Inc. publicly reported affirmative results of theanalysis of phase two tests for evaluating fenretinide for the treatmentof GA related to AMD.

From the above, application of a medicament having an action to decreaseblood RBP4 value (concentration) to the prophylaxis or treatment ofophthalmic diseases is expected. In the present specification, the“action to decrease blood RBP4 value (concentration)” is sometimesreferred to as an “RBP4-lowering action”, and the “medicament having anaction to decrease blood RBP4 value (concentration)” is sometimesreferred to as an “RBP4-lowering drug”.

Patent document 2 discloses the following compound having a bloodglucose lowering and glucose tolerance improving effect:

wherein each symbol is as defined in the document.

Patent document 3 discloses the following compound useful as atherapeutic agent for metabolic bone diseases:

wherein each symbol is as defined in the document.

Patent document 4 discloses the following compound having anRBP4-lowering action and useful for the prophylaxis or⋅ treatment ofdiabetes, obesity and the like:

wherein each symbol is as defined in the document.

Patent document 5 discloses the following compound having anRBP4-lowering action and useful for the prophylaxis or⋅ treatment ofdiabetes and the like:

wherein each symbol is as defined in the document.

Patent document 6 discloses the following compound having anRBP4-lowering action and useful for the prophylaxis or⋅ treatment ofdiabetes, age-related macular degeneration and the like:

wherein each symbol is as defined in the document.

Patent document 7 discloses the following compound used for the analysisof a polypeptide sequence:

Patent document 8 discloses the following compound having anRBP4-lowering action:

wherein each symbol is as defined in the document.

DOCUMENT LIST Patent Documents

-   patent document 1: WO 2009/042444-   patent document 2: U.S. Pat. No. 5,239,080-   patent document 3: U.S. Pat. No. 5,371,098-   patent document 4: WO 2009/051244-   patent document 5: WO 2009/145286-   patent document 6: WO 2010/119992-   patent document 7: WO 2003/031984-   patent document 8: U.S. Pat. No. 3,625,970

Non-Patent Document

-   non-patent document 1: Biochim. Biophys. Acta, 1294, 48-54 (1996)

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

An object of the present invention is to provide a heterocyclic compoundhaving a RBP4-lowering action and useful for the prophylaxis ortreatment of a disease or condition mediated by an increase in RBP4 orretinol supplied by RBP4 such as age-related macular degeneration,Stargardt's disease and the like, and a medicament containing same.

Means of Solving the Problems

The present inventors have conducted intensive studies in an attempt tosolve the above-mentioned problems and found that a compound representedby the following formula (I) has a superior RBP4-lowering action, whichresulted in the completion of the present invention.

Therefore, the present invention provides the following.

[1] A compound represented by the formula (I):

wherein

ring A is an optionally further substituted monocyclicnitrogen-containing aromatic heterocycle;

X is CH₂ or O; and

R is a hydrogen atom or a C₁₋₆ alkyl group, excluding

-   3-{4-[3,5-bis(trifluoromethyl)phenyl]-1,3-oxazol-2-yl}propanoic    acid;-   3-{4-[3,5-bis(trifluoromethyl)phenyl]-1,3-oxazol-2-yl}propanoic acid    methyl ester;-   3-{4-[3,5-bis(trifluoromethyl)phenyl]-1,3-oxazol-2-yl}propanoic acid    ethyl ester; and-   3-(3-(3,5-bis(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)propanoic    acid,    or a salt thereof (sometimes to be abbreviated as “compound (I)” in    the present specification);    [2] the compound of the above-mentioned [1], wherein R is a hydrogen    atom, or a salt thereof;    [3] the compound of the above-mentioned [1], wherein ring A is an    optionally further substituted, monocyclic nitrogen-containing    aromatic heterocycle free of a hetero atom other than nitrogen atom    as a ring-constituting atom, or a salt thereof;    [4] the compound of the above-mentioned [1] or [2], wherein ring A    is a pyrazole ring, a pyridine ring or a pyrimidine ring, or a salt    thereof;    [5] ((2-(3,5-bis(trifluoromethyl)phenyl)pyrimidin-5-yl)oxy)acetic    acid or a salt thereof;    [6] ((6-(3,5-bis(trifluoromethyl)phenyl)pyridin-3-yl)oxy)acetic acid    or a salt thereof;    [7] 3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)propanoic    acid or a salt thereof;    [8] ((4-(3,5-bis(trifluoromethyl)phenyl)-1,3-oxazol-2-yl)oxy)acetic    acid or a salt thereof;    [9] ((1-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)oxy)acetic    acid or a salt thereof;    [10] a medicament comprising the compound of [1] or [2] or a salt    thereof;    [11] the medicament of [10], which is a retinol binding protein 4    lowering drug;    [12] the medicament of [10], which is a prophylactic or therapeutic    agent for macular degeneration and/or Stargardt's disease;    [13] the compound of [1] or [2], or a salt thereof for use in the    prophylaxis or treatment of macular degeneration and/or Stargardt's    disease;    [14] a method of lowering retinol binding protein 4 in a mammal,    comprising administering an effective amount of the compound of [1]    or [2], or a salt thereof to the mammal;    [15] a method for the prophylaxis or treatment of macular    degeneration and/or Stargardt's disease in a mammal, comprising    administering an effective amount of the compound of [1] or [2], or    a salt thereof to the mammal;    [16] use of the compound of [1] or [2], or a salt thereof in    producing a prophylactic or therapeutic agent for macular    degeneration and/or Stargardt's disease;    [17] the compound of [1], wherein when ring A is an optionally    further substituted, monocyclic nitrogen-containing aromatic    heterocycle free of a hetero atom other than nitrogen atom as a    ring-constituting atom, X is CH₂ or O, and when ring A is an    optionally further substituted, monocyclic nitrogen-containing    aromatic heterocycle containing, as a ring-constituting atom, a    hetero atom other than nitrogen atom, X is O, or a salt thereof.

Effect of the Invention

According to the present invention, a prophylactic or therapeutic agentfor a disease or condition mediated by an increase in RBP4 or retinolsupplied by RBP4 such as age-related macular degeneration, Stargardt'sdisease and the like is provided.

DETAILED DESCRIPTION OF THE INVENTION

The definition of each substituent used in the present specification isdescribed in detail in the following. Unless otherwise specified, eachsubstituent has the following definition.

In the present specification, examples of the “halogen atom” includefluorine, chlorine, bromine and iodine.

In the present specification, examples of the “C₁₋₆ alkyl group” includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl,isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and2-ethylbutyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkyl group” include a C₁₋₆ alkyl group optionally having 1 to 7,preferably 1 to 5, halogen atoms. Specific examples thereof includemethyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl,ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl,pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl,isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl and6,6,6-trifluorohexyl.

In the present specification, examples of the “C₂₋₆ alkenyl group”include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and5-hexenyl.

In the present specification, examples of the “C₂₋₆ alkynyl group”include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl,2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and 4-methyl-2-pentynyl.

In the present specification, examples of the “C₃₋₁₀ cycloalkyl group”include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[3.2.1]octyl and adamantyl.

In the present specification, examples of the “optionally halogenatedC₃₋₁₀ cycloalkyl group” include a C₃₋₁₀ cycloalkyl group optionallyhaving 1 to 7, preferably 1 to 5, halogen atoms. Specific examplesthereof include cyclopropyl, 2,2-difluorocyclopropyl,2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl.

In the present specification, examples of the “C₃₋₁₀ cycloalkenyl group”include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl and cyclooctenyl.

In the present specification, examples of the “C₆₋₁₄ aryl group” includephenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl.

In the present specification, examples of the “C₇₋₁₆ aralkyl group”include benzyl, phenethyl, naphthylmethyl and phenylpropyl.

In the present specification, examples of the “C₁₋₆ alkoxy group”include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkoxy group” include a C₁₋₆ alkoxy group optionally having 1 to 7,preferably 1 to 5, halogen atoms. Specific examples thereof includemethoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the “C₃₋₁₀ cycloalkyloxygroup” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.

In the present specification, examples of the “C₁₋₆ alkylthio group”include methylthio, ethylthio, propylthio, isopropylthio, butylthio,sec-butylthio, tert-butylthio, pentylthio and hexylthio.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkylthio group” include a C₁₋₆ alkylthio group optionally having 1to 7, preferably 1 to 5, halogen atoms. Specific examples thereofinclude methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio,pentylthio and hexylthio.

In the present specification, examples of the “C₁₋₆ alkyl-carbonylgroup” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl,pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl,hexanoyl and heptanoyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkyl-carbonyl group” include a C₁₋₆ alkyl-carbonyl groupoptionally having 1 to 7, preferably 1 to 5, halogen atoms. Specificexamples thereof include acetyl, chloroacetyl, trifluoroacetyl,trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.

In the present specification, examples of the “C₁₋₆ alkoxy-carbonylgroup” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl andhexyloxycarbonyl.

In the present specification, examples of the “C₆₋₁₄ aryl-carbonylgroup” include benzoyl, l-naphthoyl and 2-naphthoyl.

In the present specification, examples of the “C₇₋₁₆ aralkyl-carbonylgroup” include phenylacetyl and phenylpropionyl.

In the present specification, examples of the “5- to 14-memberedaromatic heterocyclylcarbonyl group” include nicotinoyl, isonicotinoyl,thenoyl and furoyl.

In the present specification, examples of the “3- to 14-memberednon-aromatic heterocyclylcarbonyl group” include morpholinylcarbonyl,piperidinylcarbonyl and pyrrolidinylcarbonyl.

In the present specification, examples of the “mono- or di-C₁₋₆alkyl-carbamoyl group” include methylcarbamoyl, ethylcarbamoyl,dimethylcarbamoyl, diethylcarbamoyl and N-ethyl-N-methylcarbamoyl.

In the present specification, examples of the “mono- or di-C₇₋₁₆aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl.

In the present specification, examples of the “C₁₋₆ alkylsulfonyl group”include methylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl andtert-butylsulfonyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkylsulfonyl group” include a C₁₋₆ alkylsulfonyl group optionallyhaving 1 to 7, preferably 1 to 5, halogen atoms. Specific examplesthereof include methylsulfonyl, difluoromethylsulfonyl,trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl,pentylsulfonyl and hexylsulfonyl.

In the present specification, examples of the “C₆₋₁₄ arylsulfonyl group”include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.

In the present specification, examples of the “substituent” include ahalogen atom, a cyano group, a nitro group, an optionally substitutedhydrocarbon group, an optionally substituted heterocyclic group, an acylgroup, an optionally substituted amino group, an optionally substitutedcarbamoyl group, an optionally substituted thiocarbamoyl group, anoptionally substituted sulfamoyl group, an optionally substitutedhydroxy group, an optionally substituted sulfanyl (SH) group and anoptionally substituted silyl group.

In the present specification, examples of the “hydrocarbon group”(including “hydrocarbon group” of “optionally substituted hydrocarbongroup”) include a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynylgroup, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀ cycloalkenyl group, a C₆₋₁₄aryl group and a C₇₋₁₆ aralkyl group.

In the present specification, examples of the “optionally substitutedhydrocarbon group” include a hydrocarbon group optionally havingsubstituent(s) selected from the following substituent group A.

[Substituent Group A]

(1) a halogen atom,(2) a nitro group,(3) a cyano group,(4) an oxo group,(5) a hydroxy group,(6) an optionally halogenated C₁₋₆ alkoxy group,(7) a C₆₋₁₄ aryloxy group (e.g., phenoxy, naphthoxy),(8) a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy),(9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g.,pyridyloxy),(10) a 3- to 14-membered non-aromatic heterocyclyloxy group (e.g.,morpholinyloxy, piperidinyloxy),(11) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetoxy, propanoyloxy),(12) a C₆₋₁₄ aryl-carbonyloxy group (e.g., benzoyloxy, 1-naphthoyloxy,2-naphthoyloxy),(13) a C₁₋₆ alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy,ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),(14) a mono- or di-C₁₋₆ alkyl-carbamoyloxy group (e.g.,methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,diethylcarbamoyloxy),(15) a C₆₋₁₄ aryl-carbamoyloxy group (e.g., phenylcarbamoyloxy,naphthylcarbamoyloxy),(16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g.,nicotinoyloxy),(17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group(e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy),(18) an optionally halogenated C₁₋₆ alkylsulfonyloxy group (e.g.,methylsulfonyloxy, trifluoromethylsulfonyloxy),(19) a C₆₋₁₄ arylsulfonyloxy group optionally substituted by a C₁₋₆alkyl group (e.g., phenylsulfonyloxy, toluenesulfonyloxy),(20) an optionally halogenated C₁₋₆ alkylthio group,(21) a 5- to 14-membered aromatic heterocyclic group,(22) a 3- to 14-membered non-aromatic heterocyclic group,(23) a formyl group,(24) a carboxy group,(25) an optionally halogenated C₁₋₆ alkyl-carbonyl group,(26) a C₆₋₁₄ aryl-carbonyl group,(27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,(28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group,(29) a C₁₋₆ alkoxy-carbonyl group,(30) a C₆₋₁₄ aryloxy-carbonyl group (e.g., phenyloxycarbonyl,1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl),(31) a C₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,phenethyloxycarbonyl),(32) a carbamoyl group,(33) a thiocarbamoyl group,(34) a mono- or di-C₁₋₆ alkyl-carbamoyl group,(35) a C₆₋₁₄ aryl-carbamoyl group (e.g., phenylcarbamoyl),(36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl, thienylcarbamoyl),(37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl group (e.g.,morpholinylcarbamoyl, piperidinylcarbamoyl),(38) an optionally halogenated C₁₋₆ alkylsulfonyl group,(39) a C₆₋₁₄ arylsulfonyl group,(40) a 5- to 14-membered aromatic heterocyclylsulfonyl group (e.g.,pyridylsulfonyl, thienylsulfonyl),(41) an optionally halogenated C₁₋₆ alkylsulfinyl group,(42) a C₆₋₁₄ arylsulfinyl group (e.g., phenylsulfinyl,1-naphthylsulfinyl, 2-naphthylsulfinyl),(43) a 5- to 14-membered aromatic heterocyclylsulfinyl group (e.g.,pyridylsulfinyl, thienylsulfinyl),(44) an amino group,(45) a mono- or di-C₁₋₆ alkylamino group (e.g., methylamino, ethylamino,propylamino, isopropylamino, butylamino, dimethylamino, diethylamino,dipropylamino, dibutylamino, N-ethyl-N-methylamino),(46) a mono- or di-C₆₋₁₄ arylamino group (e.g., phenylamino),(47) a 5- to 14-membered aromatic heterocyclylamino group (e.g.,pyridylamino),(48) a C₇₋₁₆ aralkylamino group (e.g., benzylamino),(49) a formylamino group,(50) a C₁₋₆ alkyl-carbonylamino group (e.g., acetylamino,propanoylamino, butanoylamino),(51) a (C₁₋₆ alkyl) (C₁₋₆ alkyl-carbonyl) amino group (e.g.,N-acetyl-N-methylamino),(52) a C₆₋₁₄ aryl-carbonylamino group (e.g., phenylcarbonylamino,naphthylcarbonylamino),(53) a C₁₋₆ alkoxy-carbonylamino group (e.g., methoxycarbonylamino,ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino,tert-butoxycarbonylamino),(54) a C₇₋₁₆ aralkyloxy-carbonylamino group (e.g.,benzyloxycarbonylamino),(55) a C₁₋₆ alkylsulfonylamino group (e.g., methylsulfonylamino,ethylsulfonylamino),(56) a C₆₋₁₄ arylsulfonylamino group optionally substituted by a C₁₋₆alkyl group (e.g., phenylsulfonylamino, toluenesulfonylamino),(57) an optionally halogenated C₁₋₆ alkyl group,(58) a C₂₋₆ alkenyl group,(59) a C₂₋₆ alkynyl group,(60) a C₃₋₁₀ cycloalkyl group,(61) a C₃₋₁₀ cycloalkenyl group and(62) a C₆₋₁₄ aryl group.

The number of the above-mentioned substituents in the “optionallysubstituted hydrocarbon group” is, for example, 1 to 5, preferably 1 to3. When the number of the substituents is two or more, the respectivesubstituents may be the same or different.

In the present specification, examples of the “heterocyclic group”(including “heterocyclic group” of “optionally substituted heterocyclicgroup”) include (i) an aromatic heterocyclic group, (ii) a non-aromaticheterocyclic group and (iii) a 7- to 10-membered bridged heterocyclicgroup, each containing, as a ring-constituting atom besides carbon atom,1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom.

In the present specification, examples of the “aromatic heterocyclicgroup” (including “5- to 14-membered aromatic heterocyclic group”)include a 5- to 14-membered (preferably 5- to 10-membered) aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom.

Preferable examples of the “aromatic heterocyclic group” include 5- or6-membered monocyclic aromatic heterocyclic groups such as thienyl,furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like; and8- to 14-membered fused polycyclic (preferably bi or tricyclic) aromaticheterocyclic groups such as benzothiophenyl, benzofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl,furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl,thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl,thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl,pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl,pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl,isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl,naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl and the like.

In the present specification, examples of the “non-aromatic heterocyclicgroup” (including “3- to 14-membered non-aromatic heterocyclic group”)include a 3- to 14-membered (preferably 4- to 10-membered) non-aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom.

Preferable examples of the “non-aromatic heterocyclic group” include 3-to 8-membered monocyclic non-aromatic heterocyclic groups such asaziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl,tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl,imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl,pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl,tetrahydrooxazolyl, tetrahydroisooxazolyl, piperidinyl, piperazinyl,tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl,tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl,tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl,azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl and thelike; and 9- to 14-membered fused polycyclic (preferably bi ortricyclic) non-aromatic heterocyclic groups such as dihydrobenzofuranyl,dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl,dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl,tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl,isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl,tetrahydroquinoxalinyl, tetrahydrophenanthridinyl,hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl,tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl,tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacrydinyl,tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl andthe like.

In the present specification, preferable examples of the “7- to10-membered bridged heterocyclic group” include quinuclidinyl and7-azabicyclo[2.2.1]heptanyl.

In the present specification, examples of the “nitrogen-containingheterocyclic group” include the “heterocyclic group” containing at leastone nitrogen atom as a ring-constituting atom.

In the present specification, examples of the “optionally substitutedheterocyclic group” include a heterocyclic group optionally havingsubstituent(s) selected from the aforementioned substituent group A.

The number of the substituents in the “optionally substitutedheterocyclic group” is, for example, 1 to 3. When the number of thesubstituents is two or more, the respective substituents may be the sameor different.

In the present specification, examples of the “acyl group” include aformyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group,a sulfino group, a sulfo group, a sulfamoyl group and a phosphono group,each optionally having “1 or 2 substituents selected from a C₁₋₆ alkylgroup, a C₂₋₆ alkenyl group, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀cycloalkenyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a 5- to14-membered aromatic heterocyclic group and a 3- to 14-memberednon-aromatic heterocyclic group, each of which optionally has 1 to 3substituents selected from a halogen atom, an optionally halogenatedC₁₋₆ alkoxy group, a hydroxy group, a nitro group, a cyano group, anamino group and a carbamoyl group”.

Examples of the “acyl group” also include a hydrocarbon-sulfonyl group,a heterocyclylsulfonyl group, a hydrocarbon-sulfinyl group and aheterocyclylsulfinyl group.

Here, the hydrocarbon-sulfonyl group means a hydrocarbon group-bondedsulfonyl group, the heterocyclylsulfonyl group means a heterocyclicgroup-bonded sulfonyl group, the hydrocarbon-sulfinyl group means ahydrocarbon group-bonded sulfinyl group and the heterocyclylsulfinylgroup means a heterocyclic group-bonded sulfinyl group.

Preferable examples of the “acyl group” include a formyl group, acarboxy group, a C₁₋₆ alkyl-carbonyl group, a C₂₋₆ alkenyl-carbonylgroup (e.g., crotonoyl), a C₃₋₁₀ cycloalkyl-carbonyl group (e.g.,cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl,cycloheptanecarbonyl), a C₃₋₁₀ cycloalkenyl-carbonyl group (e.g.,2-cyclohexenecarbonyl), a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a C₆₋₁₄aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), aC₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,phenethyloxycarbonyl), a carbamoyl group, a mono- or di-C₁₋₆alkyl-carbamoyl group, a mono- or di-C₂₋₆ alkenyl-carbamoyl group (e.g.,diallylcarbamoyl), a mono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g.,cyclopropylcarbamoyl), a mono- or di-C₆₋₁₄ aryl-carbamoyl group (e.g.,phenylcarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-carbamoyl group, a 5- to14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl), a thiocarbamoyl group, a mono- or di-C₁₋₆alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl,N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆ alkenyl-thiocarbamoylgroup (e.g., diallylthiocarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-thiocarbamoyl group(e.g., phenylthiocarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-thiocarbamoylgroup (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a 5- to14-membered aromatic heterocyclylthiocarbamoyl group (e.g.,pyridylthiocarbamoyl), a sulfino group, a C₁₋₆ alkylsulfinyl group(e.g., methylsulfinyl, ethylsulfinyl), a sulfo group, a C₁₋₆alkylsulfonyl group, a C₆-14 arylsulfonyl group, a phosphono group and amono- or di-C₁₋₆ alkylphosphono group (e.g., dimethylphosphono,diethylphosphono, diisopropylphosphono, dibutylphosphono).

In the present specification, examples of the “optionally substitutedamino group” include an amino group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group, a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, a C₁₋₆ alkylsulfonyl group and a C₆₋₁₄ arylsulfonyl group, eachof which optionally has 1 to 3 substituents selected from substituentgroup A”.

Preferable examples of the optionally substituted amino group include anamino group, a mono- or di-(optionally halogenated C₁₋₆ alkyl)aminogroup (e.g., methylamino, trifluoromethylamino, dimethylamino,ethylamino, diethylamino, propylamino, dibutylamino), a mono- or di-C₂₋₆alkenylamino group (e.g., diallylamino), a mono- or di-C₃₋₁₀cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino), a mono-or di-C₆₋₁₄ arylamino group (e.g., phenylamino), a mono- or di-C₇-16aralkylamino group (e.g., benzylamino, dibenzylamino), a mono- ordi-(optionally halogenated C₁₋₆ alkyl)-carbonylamino group (e.g.,acetylamino, propionylamino), a mono- or di-C₆₋₁₄ aryl-carbonylaminogroup (e.g., benzoylamino), a mono- or di-C₇₋₁₆ aralkyl-carbonylaminogroup (e.g., benzylcarbonylamino), a mono- or di-5- to 14-memberedaromatic heterocyclylcarbonylamino group (e.g., nicotinoylamino,isonicotinoylamino), a mono- or di-3- to 14-membered non-aromaticheterocyclylcarbonylamino group (e.g., piperidinylcarbonylamino), amono- or di-C₁₋₆ alkoxy-carbonylamino group (e.g.,tert-butoxycarbonylamino), a 5- to 14-membered aromaticheterocyclylamino group (e.g., pyridylamino), a carbamoylamino group, a(mono- or di-C₁₋₆ alkyl-carbamoyl)amino group (e.g.,methylcarbamoylamino), a (mono- or di-C₇₋₁₆ aralkyl-carbamoyl)aminogroup (e.g., benzylcarbamoylamino), a C₁₋₆ alkylsulfonylamino group(e.g., methylsulfonylamino, ethylsulfonylamino), a C₆₋₁₄arylsulfonylamino group (e.g., phenylsulfonylamino), a (C₁₋₆ alkyl)(C₁₋₆ alkyl-carbonyl)amino group (e.g., N-acetyl-N-methylamino) and a(C₁₋₆ alkyl) (C₆₋₁₄ aryl-carbonyl)amino group (e.g.,N-benzoyl-N-methylamino).

In the present specification, examples of the “optionally substitutedcarbamoyl group” include a carbamoyl group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted carbamoyl groupinclude a carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbamoyl group, amono- or di-C₂₋₆ alkenyl-carbamoyl group (e.g., diallylcarbamoyl), amono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g.,cyclopropylcarbamoyl, cyclohexylcarbamoyl), a mono- or di-C₆₋₁₄aryl-carbamoyl group (e.g., phenylcarbamoyl), a mono- or di-C₇₋₁₆aralkyl-carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbonyl-carbamoylgroup (e.g., acetylcarbamoyl, propionylcarbamoyl), a mono- or di-C₆₋₁₄aryl-carbonyl-carbamoyl group (e.g., benzoylcarbamoyl) and a 5- to14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl).

In the present specification, examples of the “optionally substitutedthiocarbamoyl group” include a thiocarbamoyl group optionally having “1or 2 substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenylgroup, a C₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkylgroup, a C₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted thiocarbamoyl groupinclude a thiocarbamoyl group, a mono- or di-C₁₋₆ alkyl-thiocarbamoylgroup (e.g., methylthiocarbamoyl, ethylthiocarbamoyl,dimethylthiocarbamoyl, diethylthiocarbamoyl,N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆ alkenyl-thiocarbamoylgroup (e.g., diallylthiocarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-thiocarbamoyl group(e.g., phenylthiocarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-thiocarbamoylgroup (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a mono- ordi-C₁₋₆ alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl,propionylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-thiocarbamoylgroup (e.g., benzoylthiocarbamoyl) and a 5- to 14-membered aromaticheterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl).

In the present specification, examples of the “optionally substitutedsulfamoyl group” include a sulfamoyl group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted sulfamoyl groupinclude a sulfamoyl group, a mono- or di-C₁₋₆ alkyl-sulfamoyl group(e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl,diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), a mono- or di-C₂₋₆alkenyl-sulfamoyl group (e.g., diallylsulfamoyl), a mono- or di-C₃₋₁₀cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl,cyclohexylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-sulfamoyl group (e.g.,phenylsulfamoyl), a mono- or di-C₇₋₁₆ aralkyl-sulfamoyl group (e.g.,benzylsulfamoyl, phenethylsulfamoyl), a mono- or di-C₁₋₆alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl,propionylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-sulfamoyl group(e.g., benzoylsulfamoyl) and a 5- to 14-membered aromaticheterocyclylsulfamoyl group (e.g., pyridylsulfamoyl).

In the present specification, examples of the “optionally substitutedhydroxy group” include a hydroxyl group optionally having “a substituentselected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₃₋₁₀cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a C₁₋₆alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group, a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, a C₁₋₆ alkylsulfonyl group and a C₆₋₁₄ arylsulfonyl group, eachof which optionally has 1 to 3 substituents selected from substituentgroup A”.

Preferable examples of the optionally substituted hydroxy group includea hydroxy group, a C₁₋₆ alkoxy group, a C₂₋₆ alkenyloxy group (e.g.,allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), a C₃₋₁₀cycloalkyloxy group (e.g., cyclohexyloxy), a C₆₋₁₄ aryloxy group (e.g.,phenoxy, naphthyloxy), a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy,phenethyloxy), a C₁₋₆ alkyl-carbonyloxy group (e.g., acetyloxy,propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), a C₆₋₁₄aryl-carbonyloxy group (e.g., benzoyloxy), a C₇₋₁₆ aralkyl-carbonyloxygroup (e.g., benzylcarbonyloxy), a 5- to 14-membered aromaticheterocyclylcarbonyloxy group (e.g., nicotinoyloxy), a 3- to 14-memberednon-aromatic heterocyclylcarbonyloxy group (e.g.,piperidinylcarbonyloxy), a C₁₋₆ alkoxy-carbonyloxy group (e.g.,tert-butoxycarbonyloxy), a 5- to 14-membered aromatic heterocyclyloxygroup (e.g., pyridyloxy), a carbamoyloxy group, a C₁₋₆alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy), a C₇₋₁₆aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy), a C₁₋₆alkylsulfonyloxy group (e.g., methylsulfonyloxy, ethylsulfonyloxy) and aC₆₋₁₄ arylsulfonyloxy group (e.g., phenylsulfonyloxy).

In the present specification, examples of the “optionally substitutedsulfanyl group” include a sulfanyl group optionally having “asubstituent selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group and a 5- to14-membered aromatic heterocyclic group, each of which optionally has 1to 3 substituents selected from substituent group A” and a halogenatedsulfanyl group.

Preferable examples of the optionally substituted sulfanyl group includea sulfanyl (—SH) group, a C₁₋₆ alkylthio group, a C₂₋₆ alkenylthio group(e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), a C₃₋₁₀cycloalkylthio group (e.g., cyclohexylthio), a C₆₋₁₄ arylthio group(e.g., phenylthio, naphthylthio), a C₇₋₁₆ aralkylthio group (e.g.,benzylthio, phenethylthio), a C₁₋₆ alkyl-carbonylthio group (e.g.,acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), aC₆₋₁₄ aryl-carbonylthio group (e.g., benzoylthio), a 5- to 14-memberedaromatic heterocyclylthio group (e.g., pyridylthio) and a halogenatedthio group (e.g., pentafluorothio).

In the present specification, examples of the “optionally substitutedsilyl group” include a silyl group optionally having “1 to 3substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group and a C₇₋₁₆ aralkyl group,each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted silyl group include atri-C₁₋₆ alkylsilyl group (e.g., trimethylsilyl,tert-butyl(dimethyl)silyl).

In the present specification, examples of the “hydrocarbon ring” includea C₆₋₄ aromatic hydrocarbon ring, C₃₋₁₀ cycloalkane and C₃₋₁₀cycloalkene.

In the present specification, examples of the “C₆₋₄ aromatic hydrocarbonring” include benzene and naphthalene.

In the present specification, examples of the “C₃₋₁₀ cycloalkane”include cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane and cyclooctane.

In the present specification, examples of the “C₃₋₁₀ cycloalkene”include cyclopropene, cyclobutene, cyclopentene, cyclohexene,cycloheptene and cyclooctene.

In the present specification, examples of the “heterocycle” include anaromatic heterocycle and a non-aromatic heterocycle, each containing, asa ring-constituting atom besides carbon atom, 1 to 4 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom.

In the present specification, examples of the “aromatic heterocycle”include a 5- to 14-membered (preferably 5- to 10-membered) aromaticheterocycle containing, as a ring-constituting atom besides carbon atom,1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom. Preferable examples of the “aromatic heterocycle” include5- or 6-membered monocyclic aromatic heterocycles such as thiophene,furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole,isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole,1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole,tetrazole, triazine and the like; and 8- to 14-membered fused polycyclic(preferably bi or tricyclic) aromatic heterocycles such asbenzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole,benzothiazole, benzisothiazole, benzotriazole, imidazopyridine,thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine,oxazolopyridine, thiazolopyridine, imidazopyrazine, imidazopyrimidine,thienopyrimidine, furopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine,oxazolopyrimidine, thiazolopyrimidine, pyrazolopyrimidine,pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxathiin, indole,isoindole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine,naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole,O-carboline, phenanthridine, acridine, phenazine, phenothiazine,phenoxazine and the like.

In the present specification, examples of the “non-aromatic heterocycle”include a 3- to 14-membered (preferably 4- to 10-membered) non-aromaticheterocycle containing, as a ring-constituting atom besides carbon atom,1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom. Preferable examples of the “non-aromatic heterocycle”include 3- to 8-membered monocyclic non-aromatic heterocycles such asaziridine, oxirane, thiirane, azetidine, oxetane, thietane,tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine,imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline,pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole,tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine,tetrahydropyridine, dihydropyridine, dihydrothiopyran,tetrahydropyrimidine, tetrahydropyridazine, dihydropyran,tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine,azepanine, diazepane, azepine, azocane, diazocane, oxepane and the like;and 9- to 14-membered fused polycyclic (preferably bi or tricyclic)non-aromatic heterocycles such as dihydrobenzofuran,dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole,dihydrobenzisothiazole, dihydronaphtho[2,3-b]thiophene,tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolizine, indoline,isoindoline, tetrahydrothieno[2,3-c]pyridine, tetrahydrobenzazepine,tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine,hexahydrophenoxazine, tetrahydrophthalazine, tetrahydronaphthyridine,tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole,tetrahydro-D-carboline, tetrahydroacridine, tetrahydrophenazine,tetrahydrothioxanthene, octahydroisoquinoline and the like.

In the present specification, examples of the “nitrogen-containingheterocycle” include the “heterocycle” containing at least one nitrogenatom as a ring-constituting atom.

In the present specification, the “monocyclic nitrogen-containingaromatic heterocycle” of the “optionally further substituted monocyclicnitrogen-containing aromatic heterocycle” is, for example, theabove-mentioned “aromatic heterocycle” which is monocyclic and contains,as a ring-constituting atom, at least one nitrogen atom, and thesubstituent therefor includes the above-mentioned “substituent”.

Each symbol in the formula (I) is defined in detail below.

Ring A shows an optionally further substituted monocyclicnitrogen-containing aromatic heterocycle. In the formula (I), the atomon ring A to which a group represented by

is bonded is not limited to a carbon atom, and may be a hetero atom(e.g., nitrogen atom).

Examples of the “monocyclic nitrogen-containing aromatic heterocycle” ofthe “optionally further substituted monocyclic nitrogen-containingaromatic heterocycle” for ring A include a 5- or 6-membered monocyclicnitrogen-containing aromatic heterocycle (e.g., a pyrazole ring, anoxazole ring, a pyridine ring, a pyrimidine ring).

The “monocyclic nitrogen-containing aromatic heterocycle” of the“optionally further substituted monocyclic nitrogen-containing aromaticheterocycle” for ring A is optionally further substituted atsubstitutable position(s) by 1 to 3 (preferably 1 or 2) substituentsother than 3,5-bis(trifluoromethyl)phenyl group and HOOC—CH₂—X— group.

Examples of the “substituent” include halogen atom (e.g., fluorine,chlorine, bromine, iodine), optionally halogenated C₁₋₆ alkyl group(e.g., trifluoromethyl), C₃₋₆ cycloalkyl group, C₁₋₆ alkoxy group, andC₆₋₁₄ aryl group (e.g., phenyl).

As ring A, a monocyclic nitrogen-containing aromatic heterocycle whichis not further substituted, namely, a monocyclic nitrogen-containingaromatic heterocycle not substituted by a substituent other than a3,5-bis(trifluoromethyl)phenyl group and a HOOC—CH₂—X— group ispreferable. In the present specification, the “monocyclicnitrogen-containing aromatic heterocycle which is not furthersubstituted (not substituted by a substituent other than3,5-bis(trifluoromethyl)phenyl group and HOOC—CH₂—X— group)” for ring Ais sometimes abbreviated simply as “monocyclic nitrogen-containingaromatic heterocycle”.

In another embodiment of the present invention, ring A is preferably anoptionally further substituted, monocyclic nitrogen-containing aromaticheterocycle (e.g., a pyrazole ring, a pyridine ring, a pyrimidine ring)free of a hetero atom other than nitrogen atom as a ring-constitutingatom, more preferably, a pyrazole ring, a pyridine ring or a pyrimidinering.

X is CH₂ or O.

R is a hydrogen atom or a C₁₋₆ alkyl group.

Examples of the “C₁₋₆ alkyl group” for R include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl,2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl.

R is preferably a hydrogen atom.

In a preferable embodiment of the present invention, when ring A is anoptionally further substituted, monocyclic nitrogen-containing aromaticheterocycle (e.g., a pyrazole ring, a pyridine ring, a pyrimidine ring)free of a hetero atom other than nitrogen atom as a ring-constitutingatom, X is CH₂ or O, and when ring A is an optionally furthersubstituted, monocyclic nitrogen-containing aromatic heterocycle (e.g.,an oxazole ring) containing, as a ring-constituting atom, a hetero atomother than nitrogen atom, X is O.

Preferable examples of compound (I) include the following compounds.

[Compound I-1]

Compound (I) wherein ring A is an optionally further substituted 5- or6-membered monocyclic nitrogen-containing aromatic heterocycle (e.g., apyrazole ring, an oxazole ring, a pyridine ring, a pyrimidine ring);

X is CH₂ or O; and

R is a hydrogen atom or a C₁₋₆ alkyl group (e.g., methyl, ethyl).

[Compound I-2]

Compound (I) wherein ring A is a 5- or 6-membered monocyclicnitrogen-containing aromatic heterocycle (e.g., a pyrazole ring, anoxazole ring, a pyridine ring, a pyrimidine ring);

X is CH₂ or O; and

R is a hydrogen atom or a C₁₋₆ alkyl group (e.g., methyl, ethyl).

[Compound I-3]

Compound (I) wherein ring A is a pyrazole ring, an oxazole ring, apyridine ring or a pyrimidine ring;

X is CH₂ or O; and

R is a hydrogen atom or a C₁₋₆ alkyl group (e.g., methyl, ethyl).

[Compound I-4]

Compound (I) wherein ring A is an optionally further substituted,monocyclic nitrogen-containing aromatic heterocycle (e.g., a pyrazolering, a pyridine ring, a pyrimidine ring) free of a hetero atom otherthan nitrogen atom as a ring-constituting atom;

X is CH₂ or O; and

R is a hydrogen atom or a C₁₋₆ alkyl group (e.g., methyl, ethyl).

[Compound I-5]

Compound (I) wherein ring A is monocyclic nitrogen-containing aromaticheterocycle (e.g., a pyrazole ring, a pyridine ring, a pyrimidine ring)free of a hetero atom other than nitrogen atom as a ring-constitutingatom;

X is CH₂ or O; and

R is a hydrogen atom or a C₁₋₆ alkyl group (e.g., methyl, ethyl).

[Compound I-6]

Compound (I) wherein ring A is a pyrazole ring, a pyridine ring or apyrimidine ring;

X is CH₂ or O; and

R is a hydrogen atom or a C₁₋₆ alkyl group (e.g., methyl, ethyl).

[Compound I-7]

Compound (I) wherein ring A is a pyrazole ring, a pyridine ring or apyrimidine ring;

X is CH₂ or O; and

R is a hydrogen atom.

Specific examples of compound (I) include the compounds of Examples 1 to10. Of these, more preferred are the compounds of Examples 1 to 5.

When compound (I) is a salt, examples thereof include metal salts,ammonium salts, salts with organic bases, salts with inorganic acids,salts with organic acids, salts with basic or acidic amino acids. Aspreferable examples of the metal salt, alkali metal salts such as sodiumsalt, potassium salt and the like; alkaline earth metal salts such ascalcium salt, magnesium salt, barium salt and the like; aluminum saltcan be mentioned. As preferable examples of the salts with organicbases, salts with trimethylamine, triethylamine, pyridine, picoline,2,6-lutidine, ethanolamine, diethanolamine, triethanolamine,cyclohexylamine, dicyclohexylamine, N,N′-dibenzylethylenediamine and thelike can be mentioned. As preferable examples of the salts withinorganic acids, salts with hydrochloric acid, hydrobromic acid, nitricacid, sulfuric acid, phosphoric acid and the like can be mentioned. Aspreferable examples of the salts with organic acids, salts with formicacid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid,oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid,malic acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid and the like can be mentioned. As preferableexamples of the salts with basic amino acids, salts with arginine,lysine, ornithine and the like can be mentioned. As preferable examplesof the salts with acidic amino acids, salts with aspartic acid, glutamicacid and the like can be mentioned.

Of these, pharmaceutically acceptable salts are preferable. For example,when a compound has an acidic functional group therein, inorganic saltssuch as alkali metal salts (e.g., sodium salt, potassium salt and thelike), alkaline earth metal salts (e.g., calcium salt, magnesium salt,and the like) and the like, ammonium salt and the like can be mentioned.When a compound has a basic functional group therein, salts withinorganic acids such as hydrochloric acid, hydrobromic acid, nitricacid, sulfuric acid, phosphoric acid and the like, and salts withorganic acids such as acetic acid, phthalic acid, fumaric acid, oxalicacid, tartaric acid, maleic acid, citric acid, succinic acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid andthe like can be mentioned.

In the present specification, compound (I), crystal of compound (I),prodrug of compound (I) and the like are sometimes collectivelyabbreviated as “the compound of the present invention”.

[Production Method]

The production method of the compound of the present invention isexplained in the following.

The starting materials and reagents used in each step in the followingproduction method, and the obtained compounds each may form a salt.Examples of the salt include those similar to the aforementioned saltsof the compound of the present invention and the like.

When the compound obtained in each step is a free compound, it can beconverted to a desired salt by a method known per se. Conversely, whenthe compound obtained in each step is a salt, it can be converted to afree form or a desired other kind of salt by a method known per se.

The compound obtained in each step can also be used for the nextreaction as a reaction mixture thereof or after obtaining a crudeproduct thereof. Alternatively, the compound obtained in each step canbe isolated and/or purified from the reaction mixture by a separationmeans such as concentration, crystallization, recrystallization,distillation, solvent extraction, fractionation, chromatography and thelike according to a conventional method.

When the starting materials and reagent compounds of each step arecommercially available, the commercially available products can be usedas they are.

In the reaction of each step, while the reaction time varies dependingon the reagents and solvents to be used, unless otherwise specified, itis generally 1 min to 48 hr, preferably 10 min to 8 hr.

In the reaction of each step, while the reaction temperature variesdepending on the reagents and solvents to be used, unless otherwisespecified, it is generally −78° C. to 300° C., preferably −78° C. to150° C.

In the reaction of each step, while the pressure varies depending on thereagents and solvents to be used, unless otherwise specified, it isgenerally 1 atm to 20 atm, preferably 1 atm to 3 atm.

In the reaction of each step, for example, microwave synthesizers suchas Initiator manufactured by Biotage and the like are sometimes used.While the reaction temperature varies depending on the reagents andsolvents to be used, unless otherwise specified, it is generally roomtemperature to 300° C., preferably 50° C. to 250° C. While the reactiontime varies depending on the reagents and solvents to be used, unlessotherwise specified, it is generally 1 min to 48 hr, preferably 1 min to8 hr.

In the reaction of each step, unless otherwise specified, a reagent isused in 0.5 equivalent to 20 equivalents, preferably 0.8 equivalent to 5equivalents, relative to the substrate. When a reagent is used as acatalyst, the reagent is used in 0.001 equivalent to 1 equivalent,preferably 0.01 equivalent to 0.2 equivalent, relative to the substrate.When the reagent is also a reaction solvent, the reagent is used in asolvent amount.

In the reaction of each step, unless otherwise specified, it isperformed without solvent or by dissolving or suspending in a suitablesolvent. Specific examples of the solvent include those described inExamples and the following.

alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol andthe like;ethers: diethyl ether, diphenyl ether, tetrahydrofuran,1,2-dimethoxyethane and the like;aromatic hydrocarbons: chlorobenzene, toluene, xylene and the like;saturated hydrocarbons: cyclohexane, hexane and the like; amides:N,N-dimethylformamide, N-methylpyrrolidone and the like;halogenated hydrocarbons: dichloromethane, carbon tetrachloride and thelike;nitriles: acetonitrile and the like;sulfoxides: dimethyl sulfoxide and the like;aromatic organic bases: pyridine and the like;acid anhydrides: acetic anhydride and the like;organic acids: formic acid, acetic acid, trifluoroacetic acid and thelike;inorganic acids: hydrochloric acid, sulfuric acid and the like; esters:ethyl acetate and the like;ketones: acetone, methyl ethyl ketone and the like; and water.

Two or more kinds of the above-mentioned solvents may be used by mixingat an appropriate ratio.

When a base is used in the reaction of each step, for example, basesshown below or those described in Examples are used.

inorganic bases: sodium hydroxide, magnesium hydroxide and the like;basic salts: sodium carbonate, calcium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium phosphate, cesium carbonateand the like;organic bases: triethylamine, diethylamine, pyridine,4-dimethylaminopyridine, N,N-dimethylaniline,1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene,imidazole, piperidine and the like;metal alkoxides: sodium ethoxide, potassium tert-butoxide and the like;alkali metal hydrides: sodium hydride and the like;metal amides: sodium amide, lithium diisopropyl amide, lithiumhexamethyl disilazide and the like; andorganic lithiums: n-butyllithium and the like.

When an acid or acidic catalyst is used in the reaction of each step,for example, acids and acidic catalysts shown below or those describedin Examples are used.

inorganic acids: hydrochloric acid, sulfuric acid, nitric acid,hydrobromic acid, phosphoric acid and the like;organic acids: acetic acid, trifluoroacetic acid, citric acid,p-toluenesulfonic acid, 10-camphorsulfonic acid and the like; andLewis acids: boron trifluoride diethyl ether complex, zinc iodide,anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous ironchloride and the like.

Unless otherwise specified, the reaction of each step is performedaccording to a method known per se, for example, the methods describedin Jikken Kagaku Kouza 5th edition, vol. 13-vol. 19 (The ChemicalSociety of Japan ed.); Shinjikken Kagaku Kouza (Courses in ExperimentalChemistry), vol. 14-vol. 15 (The Chemical Society of Japan ed.); FineOrganic Chemistry rev. 2nd edition (L. F. Tietze, Th. Eicher, NANKODO);rev. Organic Name Reactions, Their Mechanism and Essence (Hideo Togo,Kodansha); ORGANIC SYNTHESES Collective Volume I-VII (John Wiley & SonsInc); Modern Organic Synthesis in the Laboratory, A Collection ofStandard Experimental Procedures (Jie Jack Li, OXFORD UNIVERSITY);Comprehensive Heterocyclic Chemistry III, Vol. 1-Vol. 14 (Elsevier JapanKK); Strategic Applications of Named Reactions in Organic Synthesis(translation supervisor Kiyoshi Tomioka, KAGAKUDOJIN); ComprehensiveOrganic Transformations (VCH Publishers Inc.), 1989 and the like, or themethods described in the Examples.

In each step, protection or deprotection of a functional group isperformed by the method known per se, for example, the methods describedin “Protective Groups in Organic Synthesis, 4th Ed.” (Theodora W.Greene, Peter G. M. Wuts) Wiley-Interscience, 2007; “Protecting Groups3rd Ed.” (P. J. Kocienski) Thieme, 2004 and the like, or the methodsdescribed in the Examples.

Examples of the protecting group of the hydroxyl group of alcohol andthe like and a phenolic hydroxyl group include ether protecting groupssuch as methoxymethyl ether, benzyl ether, t-butyldimethylsilyl ether,tetrahydropyranyl ether and the like; carboxylate protecting groups suchas acetate and the like; sulfonate ester protecting groups such asmethanesulfonate ester and the like; carbonate ester protecting groupssuch as t-butylcarbonate and the like, and the like.

Examples of the protecting group of the carbonyl group of aldehydeinclude acetal protecting groups such as dimethyl acetal and the like;cyclic acetal protecting groups such as cyclic 1,3-dioxane and the like,and the like.

Examples of the protecting group of the carbonyl group of ketone includeketal protecting groups such as dimethyl ketal and the like; cyclicketal protecting groups such as cyclic 1,3-dioxane and the like; oximeprotecting groups such as O-methyloxime and the like; hydrazoneprotecting groups such as N,N-dimethylhydrazone and the like, and thelike.

Examples of the carboxyl protecting group include ester protectinggroups such as methyl ester and the like; amide protecting groups suchas N,N-dimethylamide and the like, and the like.

Examples of the thiol protecting group include ether protecting groupssuch as benzyl thioether and the like; ester protecting groups such asthioacetate ester, thiocarbonate, thiocarbamate and the like, and thelike.

Examples of the protecting group of an amino group and an aromatichetero ring such as imidazole, pyrrole, indole and the like includecarbamate protecting groups such as benzyl carbamate and the like; amideprotecting groups such as acetamide and the like; alkylamine protectinggroups such as N-triphenylmethylamine and the like, sulfonamideprotecting groups such as methanesulfonamide and the like, and the like.

The protecting group can be removed by a method known per se, forexample, a method using acid, base, ultraviolet light, hydrazine,phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammoniumfluoride, palladium acetate, trialkylsilyl halide (e.g., trimethylsilyliodide, trimethylsilyl bromide), a reduction method and the like.

When a reduction reaction is performed in each step, examples of thereducing agent to be used include metal hydrides such as lithiumaluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride,diisobutylaluminum hydride (DIBAL-H), sodium borohydride,tetramethylammonium triacetoxyborohydride and the like; boranes such asborane tetrahydrofuran complex and the like; Raney nickel; Raney cobalt;hydrogen; formic acid; triethylsilane and the like. When a carbon-carbondouble bond or triple bond is reduced, a method using a catalyst such aspalladium-carbon, Lindlar catalyst and the like.

When an oxidation reaction is performed in each step, examples of anoxidant to be used include peracids such as m-chloroperbenzoic acid(mCPBA), hydrogen peroxide, t-butyl hydroperoxide and the like;perchlorates such as tetrabutylammonium perchlorate and the like;chlorates such as sodium chlorate and the like; chlorites such as sodiumchlorite and the like; periodic acids such as sodium periodate and thelike; high valent iodine reagents such as iodosylbenzene and the like;reagents containing manganese such as manganese dioxide, potassiumpermanganate and the like; leads such as lead tetraacetate and the like;reagents containing chrome such as pyridinium chlorochromate (PCC),pyridinium dichromate (PDC), Jones reagent and the like; halogencompounds such as N-bromosuccinimide (NBS) and the like; oxygen; ozone;sulfur trioxide pyridine complex; osmium tetraoxide; selenium dioxide;2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the like.

When a radical cyclization reaction is performed in each step, examplesof the radical initiator to be used include azo compounds such asazobisisobutyronitrile (AIBN) and the like; water-soluble radicalinitiators such as 4,4′-azobis-4-cyanopentanoic acid (ACPA) and thelike; triethylboron in the presence of air or oxygen; benzoyl peroxideand the like. In addition, examples of the radical reaction agent to beused include tributylstannane, tristrimethylsilylsilane,1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide and thelike.

When the Wittig reaction is performed in each step, examples of theWittig reagent to be used include alkylidenephosphoranes and the like.Alkylidenephosphoranes can be prepared by a method known per se, forexample, by reacting a phosphonium salt with a strong base.

When the Horner-Emmons reaction is performed in each step, examples ofthe reagent to be used include phosphonoacetic acid esters such asmethyl dimethylphosphonoacetate, ethyl diethylphosphonoacetate and thelike; and bases such as alkali metal hydrides, organic lithiums and thelike.

When the Friedel-Crafts reaction is performed in each step, examples ofthe reagent to be used include a combination of Lewis acid and acidchloride or a combination of Lewis acid and alkylating agents (e.g.,alkyl halides, alcohol, olefins and the like). Alternatively, an organicacid and an inorganic acid can also be used instead of the Lewis acid,and acid anhydride such as acetic anhydride and the like can also beused instead of acid chloride.

When an aromatic nucleophilic substitution reaction is performed in eachstep, a nucleophilic agent (e.g., amines, imidazole and the like) and abase (e.g., basic salts, organic bases and the like) are used as thereagent.

When a nucleophilic addition reaction with carbanion, a nucleophilic1,4-addition reaction with carbanion (Michael addition reaction) or anucleophilic substitution reaction with carbanion is performed in eachstep, examples of the base to be used for developing carbanion includeorganic lithiums, metal alkoxides, inorganic bases, organic bases andthe like.

When the Grignard reaction is performed in each step, examples of theGrignard reagent include aryl magnesium halides such as phenyl magnesiumbromide and the like; and alkyl magnesium halides such as methylmagnesium bromide and the like. The Grignard reagent can be prepared bya method known per se, for example, by reacting alkyl halide or arylhalide with metal magnesium in ether or tetrahydrofuran as a solvent.

When the Knoevenagel condensation reaction is performed in each step, anactive methylene compound held between two electron-withdrawing groups(e.g., malonic acid, diethyl malonate, malononitrile and the like) and abase (e.g., organic bases, metal alkoxides, inorganic bases) are used asthe reagents.

When the Vilsmeier-Haack reaction is performed in each step, phosphorylchloride and an amide derivative (e.g., N,N-dimethylformamide and thelike) are used as the reagents.

When an azidation reaction of alcohols, alkylhalides or sulfonate estersis performed in each step, examples of the azidation agent to be usedinclude diphenylphosphoryl azide (DPPA), trimethylsilylazide, sodiumazide and the like. For example, when alcohols are azidated, a methodusing diphenylphosphoryl azide and 1,8-diazabicyclo[5,4,0]undec-7-ene(DBU), a method using trimethylsilylazide and the Lewis acid and thelike can be employed.

When a reductive amination reaction is performed in each step, examplesof the reducing agent to be used include sodium triacetoxyborohydride,sodium cyanoborohydride, hydrogen, formic acid and the like. When thesubstrate is an amine compound, examples of the carbonyl compound to beused besides para-formaldehyde include aldehydes such as acetaldehydeand the like, ketones such as cyclohexanone and the like. When thesubstrate is a carbonyl compound, examples of the amines to be usedinclude ammonia, primary amines such as methylamine and the like;secondary amines such as dimethylamine and the like, and the like.

When the Mitsunobu reaction is performed in each step, azodicarboxylateesters (e.g., diethyl azodicarboxylate (DEAD), diisopropylazodicarboxylate (DIAD) and the like) and triphenylphosphine are used asthe reagents.

When an esterification reaction, amidation reaction or ureation reactionis performed in each step, examples of the reagent to be used includehalogenated acyl forms such as acid chloride, acid bromide and the like;and activated carboxylic acids such as acid anhydride, active esterform, sulfuric acid ester form and the like. Examples of the carboxylicacid activator include carbodiimide condensing agents such as1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD) andthe like; triazine condensing agents such as4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholiniumchloride-n-hydrate (DMT-MM) and the like; carbonate ester condensingagents such as 1,1-carbonyldiimidazole (CDI) and the like;diphenylphosphoryl azide (DPPA);benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent);2-chloro-1-methyl-pyridinium iodide (Mukaiyama reagent); thionylchloride; lower alkyl haloformates such as ethyl chloroformate and thelike; O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU); sulfuric acid; a combination thereof and thelike. When a carbodiimide condensing agent is used, additives such as1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu),dimethylaminopyridine (DMAP) and the like can be further added to thereaction.

When a coupling reaction is performed in each step, examples of themetal catalyst to be used include palladium compounds such aspalladium(II) acetate, tetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine)palladium(II),dichlorobis(triethylphosphine)palladium(II),tris(dibenzylideneacetone)dipalladium(0),1,1′-bis(diphenylphosphino)ferrocene palladium(II) chloride,palladium(II) acetate and the like; nickel compounds such astetrakis(triphenylphosphine)nickel(0) and the like; rhodium compoundssuch as tris(triphenylphosphine)rhodium(III) chloride and the like; acobalt compound; copper compounds such as copper oxide, copper(I) iodideand the like; a platinum compound and the like. A base may be furtheradded to the reaction and examples of such base include inorganic bases,basic salts and the like.

When a thiocarbonylation reaction is performed in each step,diphosphorus pentasulfide is representatively used as athiocarbonylating agent. Besides diphosphorus pentasulfide, a reagenthaving a 1,3,2,4-dithiadiphosphetane-2,4-disulfide structure such as2,4-bis(4-methoxyphenyl-1,3,2,4-dithiadiphosphetane-2,4-disulfide(Lawesson reagent) and the like may also be used.

When the Wohl-Ziegler reaction is performed in each step, examples ofthe halogenating agent to be used include N-iodosuccinimide,N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfurylchloride and the like. Furthermore, the reaction can be accelerated byadding heat, light, radical initiators such as benzoyl peroxide,azobisisobutyronitrile and the like to the reaction.

When a halogenating reaction of a hydroxy group is performed in eachstep, examples of the halogenating agent to be used include acid halideof hydrohalic acid and inorganic acid; specifically, hydrochloric acid,thionyl chloride, phosphorus oxychloride and the like for chlorination,and 48% hydrobromic acid and the like for bromination. In addition, amethod of obtaining a halogenated alkyl form from alcohol by reactingwith triphenylphosphine and carbon tetrachloride or carbon tetrabromide,and the like may be used. Alternatively, a method of synthesizing ahalogenated alkyl form via a two-step reaction including conversion ofalcohol to sulfonic acid ester, and reacting same with lithium bromide,lithium chloride or sodium iodide may also be used.

When the Arbuzov reaction is performed in each step, examples of thereagent to be used include alkyl halides such as ethyl bromoacetate andthe like; and phosphites such as triethyl phosphite,tri(isopropyl)phosphite and the like.

When a sulfonation reaction is performed in each step, examples of thesulfonylating agent to be used include methanesulfonyl chloride,p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonicanhydride and the like.

When hydrolysis is performed in each step, an acid or a base is used asthe reagent. In addition, when acid hydrolysis of t-butyl ester isperformed, formic acid, triethylsilane and the like are sometimes addedto reductively trap the by-produced t-butyl cation.

When a dehydrating reaction is performed in each step, examples of thedehydrating agent to be used include sulfuric acid, phosphoruspentaoxide, phosphorus oxychloride, N,N′-dicyclohexylcarbodiimide,alumina, polyphosphoric acid and the like.

When nitration reaction is performed in each step, examples of thenitrating agent to be used include nitric acid, fuming nitric acid, andcopper nitrate. The reaction is activated by concentrated sulfuric acid,acetic anhydride and the like.

When halogenation reaction is performed in each step, examples of thehalogenating agent to be used include N-iodosuccinimide,N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), iodinemonochloride, iodine, bromine, sulfuryl chloride and the like can bementioned. In this reaction, an additive such as trifluoroacetic acidand the like may be used for the activation of a halogenating agent.

When acylation reaction is performed in each step, amidation reaction,ureation reaction, carbamation reaction, thiocarbamation reaction andthe like are performed. When carbamation reaction or thiocarbamationreaction is performed, examples of the reagent to be used includetriphosgene, carbonate condensing agents such as 1,1-carbonyldiimidazole(CDI) and the like, chlorocarbonates, chlorocarbonic acid thio esters,isothiocyanates and the like

When cyclization reaction is performed in each step, it is performed bythe Mitsunobu reaction or an alkylation reaction. When an alkylationreaction is performed, a base is used as the reagent.

Compound (4) can be produced from compound (1) by the method shown inscheme 1 or a method analogous thereto or the method described in theExamples. In the formula, R¹ shows an optionally substituted hydrocarbongroup.

Compound (2) can be produced by an alkylation reaction of compound (1),tert-butyl 2-bromoacetate and a base. Examples of the solvent to be usedinclude N,N-dimethylformamide and the like.

A commercially available product may be directly used as compound (1),or compound (1) can be produced by a method known per se or a methodanalogous thereto.

Compound (3) can be produced by a coupling reaction of compound (2),(3,5-bis(trifluoromethyl)phenyl)boronic acid, palladium catalyst and abase. Examples of the palladium catalyst to be used includetetrakis(triphenylphosphine)palladium (0) and the like, and examples ofthe solvent include 1,2-dimethoxyethane and water and the like.

Compound (4) can be produced by hydrolysis of compound (3) andtrifluoroacetic acid.

Compound (8) can be produced from compound (5) by the method shown inscheme 2 or a method analogous thereto or the method described in theExamples. In the formula, R¹ shows an optionally substituted hydrocarbongroup.

Compound (6) can be produced by a coupling reaction of compound (5),(3,5-bis(trifluoromethyl)phenyl)boronic acid, a palladium catalyst and abase. Examples of the palladium catalyst to be used includetetrakis(triphenylphosphine)palladium (0) and the like, and examples ofthe solvent include 1,2-dimethoxyethane, water and the like.

A commercially available product may be directly used as compound (5),or compound (5) can be produced by a method known per se or a methodanalogous thereto.

Compound (7) can be produced by an alkylation reaction of compound (6),tert-butyl 2-bromoacetate and a base. Examples of the solvent to be usedinclude N,N-dimethylformamide and the like.

Compound (8) can be produced by hydrolysis of compound (7) and a base.Examples of the solvent to be used include water, ethanol,tetrahydrofuran and the like.

Compound (13) can be produced from compound (9) by the method shown inscheme 3 or a method analogous thereto or the method described in theExamples.

Compound (10) can be produced by an enaminone formation reaction ofcompound (9) and N,N-dimethylformamide dimethyl acetal.

A commercially available product may be directly used as compound (9),or compound (9) can be produced by a method known per se or a methodanalogous thereto.

Compound (11) can be produced by a pyrazole ring formation reaction ofcompound (10) and hydrazine monohydrate. Examples of the solvent to beused include acetic acid and the like.

Compound (12) can be produced by an alkylation reaction of compound(11), 3-bromopropionitrile and a base. Examples of the solvent to beused include N,N-dimethylformamide and the like.

Compound (13) can be produced by hydrolysis of compound (12) andhydrochloric acid. Examples of the solvent to be used include water andthe like.

Compound (20) can be produced from compound (9) by the method shown inscheme 4 or a method analogous thereto or the method described in theExamples. In the formula, R¹ shows an optionally substituted hydrocarbongroup.

Compound (14) can be produced by a brominating reaction of compound (9)and bromine. Examples of the solvent to be used include acetic acid andthe like.

Compound (15) can be produced by a hydroxylation reaction of compound(14) and sodium formate. Examples of the solvent to be used includemethanol and the like.

Compound (16) can be produced by a carbonate formation reaction ofcompound (15), phenyl chloroformate and a base. Examples of the base tobe used include pyridine and the like, and examples of the solventinclude tetrahydrofuran and the like.

Compound (17) can be produced by an oxazole ring formation reaction ofcompound (16) and ammonium acetate. Examples of the solvent to be usedinclude acetic acid and the like.

Compound (18) can be produced by a chlorination reaction of compound(17), phosphoryl chloride and N,N-diethylaniline. Compound (19) can beproduced by an aromatic nucleophilic substitution reaction of compound(18), tert-butyl 2-hydroxyacetate and sodium hydride. Examples of thesolvent to be used include tetrahydrofuran and the like.

Compound (20) can be produced by hydrolysis of compound (19) and a base.Examples of the solvent to be used include water, methanol,tetrahydrofuran and the like.

Compound (25) can be produced from compound (21) by the method shown inscheme 5 or a method analogous thereto or the method described in theExamples. In the formula, R¹ shows an optionally substituted hydrocarbongroup.

Compound (22) can be produced by a desalting reaction of compound (21)and sodium hydroxide. Examples of the solvent to be used include water,ethyl acetate and the like.

A commercially available product may be directly used as compound (21),or compound (21) can be produced by a method known per se or a methodanalogous thereto.

Compound (23) can be produced by a pyrazole ring formation reaction ofcompound (22), ethyl propiolate and a base. Examples of the solvent tobe used include tert-butanol and the like.

Compound (24) can be produced by an alkylation reaction of compound(23), tert-butyl 2-bromoacetate and a base. Examples of the solvent tobe used include N,N-dimethylformamide and the like.

Compound (25) can be produced by hydrolysis of compound (24) and a base.Examples of the solvent to be used include water, methanol,tetrahydrofuran and the like.

When compound (I) contains optical isomer, stereoisomer, positionalisomer, or rotamer, these are also encompassed in compound (I), and canbe obtained as a single product by synthesis methods and separationmethods (e.g., concentration, solvent extraction, column chromatography,recrystallization etc.) known per se. For example, when compound (I)contains an optical isomer, an optical isomer resolved from the compoundis also encompassed in compound (I).

An optical isomer can be produced by a method known per se. To bespecific, an optical isomer is obtained using an optically activesynthetic intermediate, or by optical resolution of a racemate of thefinal product by a conventional method.

The method of optical resolution may be a method known per se, such as afractional recrystallization method, a chiral column method, adiastereomer method etc.

Compound (I) may be a crystal.

The crystal of compound (I) can be produced by crystallization ofcompound (I) by applying a crystallization method known per se.

Examples of the crystallization method include a method ofcrystallization from a solution, a method of crystallization from vapor,and a method of crystallization from a molten form.

As the analysis method of the obtained crystal, a crystal analysismethod by powder X-ray diffraction is general. Furthermore, as a methodof determining the crystal orientation, a mechanical method, an opticalmethod and the like can also be mentioned.

The crystal of compound (I) obtained by the above-mentioned productionmethod has high purity, high quality, and low hygroscopicity, is notdenatured even after preservation under general conditions for a longterm, and is extremely superior in stability. It is also superior inbiological properties (e.g., pharmacokinetics (absorption, distribution,metabolism, excretion), efficacy expression), and thus is extremelyuseful as a medicament.

A prodrug of compound (I) means a compound which is converted to thecompound (I) with a reaction due to an enzyme, an gastric acid, etc.under the physiological condition in the living body, that is, acompound which is converted to the compound (I) with oxidation,reduction, hydrolysis, etc. according to an enzyme; a compound which isconverted to the compound (I) by hydrolysis etc. due to gastric acid,etc. A prodrug for compound (I) may be a compound obtained by subjectingan amino group in compound (I) to an acylation, alkylation orphosphorylation (e.g., a compound obtained by subjecting an amino groupin compound (I) to an eicosanoylation, alanylation,pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylationand tert-butylation, etc.); a compound obtained by subjecting a hydroxygroup in compound (I) to an acylation, alkylation, phosphorylation orboration [e.g., a compound obtained by subjecting an hydroxy group incompound (I) to an acetylation, palmitoylation, propanoylation,pivaloylation, succinylation, fumarylation, alanylation,dimethylaminomethylcarbonylation, etc.]; a compound obtained bysubjecting a carboxyl group in compound (I) to an esterification oramidation [e.g., a compound obtained by subjecting a carboxyl group incompound (I) to an ethyl esterification, phenyl esterification,carboxymethyl esterification, dimethylaminomethyl esterification,pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification,phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterification, cyclohexyloxycarbonylethyl esterification andmethylamidation, etc.] and the like. Any of these compounds can beproduced from compound (I) by a method known per se.

A prodrug for compound (I) may also be one which is converted tocompound (I) under physiological conditions, such as those described in“Development of Pharmaceutical Product”, Vol. 7, Design of Molecules, p.163-198, Published by HIROKAWA SHOTEN (1990).

Compound (I) may be any of a hydrate, a non-hydrate, a solvate and anon-solvate.

Compound (I) also encompasses a compound labeled with an isotope (e.g.,³H, ¹⁴C, ³⁵S, ¹²⁵I etc.) and the like.

Compound (I) also encompasses a deuterium conversion form wherein ¹H isconverted to ²H(D).

Compound (I) also encompasses a tautomer.

Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystalsalt. Here, the cocrystal or cocrystal salt means a crystallinesubstance consisting of two or more particular substances which aresolids at room temperature, each having different physical properties(e.g., structure, melting point, heat of melting, hygroscopicity,solubility, stability etc.). The cocrystal and cocrystal salt can beproduced by cocrystallization method known per se.

Compound (I) may also be used as a PET tracer.

The compound of the present invention has a superior retinol bindingprotein 4-lowering action. The compound of the present invention alsohas a superior retinol binding protein 4 binding inhibitory action(retinol binding protein 4-TTR (transthyretin) binding inhibitoryaction).

Therefore, the compound of the present invention is useful as a safemedicament based on these actions. For example, the medicament of thepresent invention containing the compound of the present invention canbe used as a prophylactic or therapeutic agent for retinol bindingprotein 4 associated diseases in mammals (e.g., mouse, rat, hamster,rabbit, cat, dog, bovine, sheep, monkey, human etc.).

When used in the present specification, treatment also includessuppression of the progression of a disease or condition.

Specifically, the compound of the present invention can be usedprophylactic or therapeutic agent for a disease or condition mediated byan increase in RBP4 or retinol supplied by RBP4, for example, maculardegeneration (e.g., dry (atrophic or non-vascular) age-related maculardegeneration, exudative (wet or neovascular) age-related maculardegeneration), geographic atrophy and/or denaturation of photoreceptor,macular dystrophy and retinal dystrophy, retinopathy (e.g., diabeticretinopathy, retinopathy of prematurity), retinitis pigmentosa, retinalvein occlusion, retinal artery obstruction, glaucoma, or Stargardt'sdisease (Stargardt disease).

The compound of the present invention can also be used as an agent forthe prophylaxis or treatment of obesity, hyperlipidemia (e.g.,hypertriglyceridemia, hypercholesterolemia, high LDL-cholesterolemia,hypo HDL-cholesterolemia, postprandial hyperlipidemia), hypertension,cardiac failure, diabetic complications [e.g., neuropathy, nephropathy,retinopathy, diabetic cardiomyopathy, cataract, macroangiopathy,osteopenia, hyperosmolar diabetic coma, infections (e.g., respiratoryinfection, urinary tract infection, gastrointestinal infection, dermalsoft tissue infections, inferior limb infection), diabetic gangrene,xerostomia, hypacusis, cerebrovascular disorder, peripheral bloodcirculation disorder], metabolic syndrome, sarcopenia and the like.

The compound of the present invention can also be used as an agent forthe prophylaxis or treatment of, for example, osteoporosis, cachexia(e.g., cancerous cachexia, tuberculous cachexia, diabetic cachexia,hemopathic cachexia, endocrinopathic cachexia, infectious cachexia orcachexia induced by acquired immunodeficiency syndrome), fatty liver,polycystic ovary syndrome, renal disease (e.g., diabetic nephropathy,glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensivenephrosclerosis, end-stage renal disorder), muscular dystrophy,myocardial infarction, angina pectoris, cerebrovascular disorder (e.g.,cerebral infarction, cerebral apoplexy), Alzheimer's disease,Parkinson's disease, anxiety, dementia, insulin resistance syndrome,syndrome X, hyperinsulinemia, perception disorder in hyperinsulinemia,tumor (e.g., leukemia, breast cancer, prostate cancer, skin cancer),irritable bowel syndrome, acute or chronic diarrhea, inflammatorydisease (e.g., chlonic rheumatoid arthritis, spondylitis deformans,osteoarthritis, lumbago, gout, postoperative or post-traumaticinflammation, swelling, neuralgia, pharyngolaryngitis, bladderinflammation, hepatitis (including nonalcoholic steatohepatitis),pneumonia, pancreatitis, enteritis, inflammatory bowel disease(including inflammatory colitis), ulcerative colitis, gastric mucosainjury (including gastric mucosa injury caused by aspirin)), smallintestinal mucosa injury, malabsorption, testis dysfunction, visceralobesity syndrome, and sarcopenia.

The compound of the present invention can also be used as an agent forlowering the level of serum retinol, serum RBP (retinol binding protein)and/or serum TTR (transthyretin) and can also be used as, for example, aprophylactic or therapeutic agent for hyperretinolemia (excess serumretinol level).

The compound of the present invention can also be used for the secondaryprevention or prevention of the progression of the above-mentionedvarious diseases (e.g., cardiovascular events such as myocardialinfarction and the like).

The compound of the present invention can be directly used as themedicament of the present invention, or as a pharmaceutical compositionformed by mixing with a pharmacologically acceptable carrier by a meansknown per se, which is generally used for a production method of apharmaceutical preparation.

The medicament of the present invention can be safely administeredorally or parenterally to mammals (e.g., human, monkey, bovine, horse,swine, mouse, rat, hamster, rabbit, cat, dog, sheep, goat etc.).

As a medicament containing the compound of the present invention, thecompound of the present invention can be used alone or as apharmaceutical composition mixed with pharmacologically acceptablecarriers, according to a method known per se as a production method of apharmaceutical preparation (e.g., methods described in the JapanesePharmacopeia, etc.). A medicament containing the compound of the presentinvention can be safely administered in the form of, for example, tablet(including sugar-coated tablet, film-coated tablet, sublingual tablet,orally disintegrating tablet, buccal tablet and the like), pill, powder,granule, capsule (including soft capsule, microcapsule), troche, syrup,liquid, emulsion, suspension, release control preparation (e.g.,immediate-release preparation, sustained-release preparation,sustained-release microcapsule), aerosol, film (e.g., orallydisintegrating film, oral mucosa-adhesive film), injection (e.g.,subcutaneous injection, intravenous injection, intramuscular injection,intraperitoneal injection), drip infusion, transdermal absorption typepreparation, cream, ointment, lotion, adhesive preparation, suppository(e.g., rectal suppository, vaginal suppository), pellet, nasalpreparation, pulmonary preparation (inhalant), eye drop and the like,orally or parenterally (e.g., intravenous, intramuscular, subcutaneous,intraorgan, intranasal, intradermal, instillation, intracerebral,intrarectal, intravaginal, intraperitoneal and intratumoradministrations, administration to the vicinity of tumor, andadministration to the lesion).

The representative content of the compound of the present invention inthe medicament of the present invention is about 0.01 wt % to about 100wt %, of the whole medicament.

While the dose of the compound of the present invention varies dependingon the subject of administration, administration route, target disease,symptom and the like, a single dose is generally about 0.01 to 100 mg/kgbody weight, preferably 0.05 to 30 mg/kg body weight, more preferably0.1 to 10 mg/kg body weight, for oral administration to adult maculardegeneration patients, and the dose is desirably administered in 1 to 3times per day.

As the above-mentioned pharmacologically acceptable carrier, which maybe used for the production of the medicament of the present invention,various organic or inorganic carrier substances conventionally used as apreparation material can be mentioned. For example, excipient,lubricant, binder and disintegrant for solid preparations; solvent,solubilizing agents, suspending agent, isotonic agent, and buffer andsoothing agent for liquid preparations can be mentioned. Wherenecessary, conventional additives such as preservatives, antioxidants,colorants, sweetening agents, adsorbing agents, wetting agents and thelike can be used appropriately in suitable amounts.

As the excipient, for example, lactose, sucrose, D-mannitol, starch,corn starch, crystalline cellulose, light anhydrous silicic acid can bementioned.

As the lubricant, for example, magnesium stearate, calcium stearate,talc, colloidal silica can be mentioned.

As the binder, for example, crystalline cellulose, sucrose, D-mannitol,dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose,polyvinylpyrrolidone, starch, saccharose, gelatin, methylcellulose,carboxymethylcellulose sodium can be mentioned.

As the disintegrant, for example, starch, carboxymethylcellulose,carboxymethylcellulose calcium, carboxymethylstarch sodium,L-hydroxypropylcellulose can be mentioned.

As the solvent, for example, water for injection, alcohol, propyleneglycol, macrogol, sesame oil, corn oil, olive oil can be mentioned.

As the solubilizing agents, for example, polyethylene glycol, propyleneglycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane,cholesterol, triethanolamine, sodium carbonate, sodium citrate can bementioned.

As the suspending agent, for example, surfactants such asstearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionate,lecithin, benzalkonium chloride, benzethonium chloride, glycerolmonostearate and the like; hydrophilic polymers such as polyvinylalcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium,methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose and the like can be mentioned.

As the isotonic agent, for example, glucose, D-sorbitol, sodiumchloride, glycerin, D-mannitol can be mentioned.

As the buffer, for example, buffers such as phosphates, acetates,carbonates, citrates and the like, can be mentioned.

As the soothing agent, for example, benzyl alcohol can be mentioned.

As the preservatives, for example, paraoxybenzoates, chlorobutanol,benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, sorbic acid canbe mentioned.

As the antioxidant, for example, sulfites, ascorbic acid, α-tocopherolcan be mentioned.

As the colorant, for example, water-soluble edible tar pigments (e.g.,foodcolors such as Food Color Red Nos. 2 and 3, Food Color Yellow Nos. 4and 5, Food Color Blue Nos. 1 and 2 and the like), water insoluble lakepigments (e.g., aluminum salt of the aforementioned water-soluble edibletar pigment and the like), natural pigments (e.g., β-carotene,chlorophil, ferric oxide red etc.) can be mentioned.

As the sweetening agent, for example, saccharin sodium, dipotassiumglycyrrhizinate, aspartame, stevia can be mentioned.

As the adsorbent, porous starch, calcium silicate (trade name: FloriteRE), magnesium aluminometasilicate (trade name: Neusilin), lightanhydrous silicic acid (trade name: Sylysia) can be mentioned.

As the wetting agent, propylene glycol monostearate, sorbitanmonooleate, diethylene glycol monolaurate, polyoxyethylene lauryl ethercan be mentioned.

When the present compound is used as an ointment, it is produced bymixing the present compound with a conventional ointment base at aconcentration of about 0.001 to 3% (W/W), preferably about 0.01 to 1%(W/W). The production of ointment preferably includes a step ofpowderizing the present compound or a step of sterilizing thepreparation. Ointment is administered 1 to 4 times per day according tothe condition of the patients.

As the ointment base, purified lanolin, white petrolatum, macrogol,Plastibase, liquid paraffin can be mentioned.

With the aim of enhancing the action of the compound of the presentinvention or decreasing the dose of the compound and the like, thecompound can be used in combination with medicaments such as therapeuticagents for diabetes, therapeutic agents for diabetic complications,therapeutic agents for hyperlipidemia, antihypertensive agents,antiobesity agents, diuretics, therapeutic agents for maculardegeneration, antioxidants, nitric oxide inducing agents, matrixmetalloproteinase (MMPs) inhibitors, anti-angiogenesis agents,chemotherapeutic agents, immunotherapeutic agents, antithromboticagents, therapeutic agents for osteoporosis, antidementia agents,erectile dysfunction improving agents, therapeutic agents forincontinence, frequent urination, therapeutic agents for dysuria and thelike (hereinafter to be abbreviated as combination drugs). Theseconcomitant drugs may be low-molecular compounds, or high-molecularproteins, polypeptides, antibodies, vaccines or the like.

The time of administration of the compound of the present invention andthat of the combination drug are not limited, and they may beadministered simultaneously or in a staggered manner to theadministration subject.

The administration form is not particularly limited, and the compound ofthe present invention and a concomitant drug only need to be combined.Examples of such administration mode include the following:

(1) administration of a single preparation obtained by simultaneouslyprocessing the compound of the present invention and the combinationdrug,(2) simultaneous administration of two kinds of preparations of thecompound of the present invention and the combination drug, which havebeen separately produced, by the same administration route,(3) administration of two kinds of preparations of the compound of thepresent invention and the combination drug, which have been separatelyproduced, by the same administration route in a staggered manner,(4) simultaneous administration of two kinds of preparations of thecompound of the present invention and the combination drug, which havebeen separately produced, by different administration routes,(5) administration of two kinds of preparations of the compound of thepresent invention and the combination drug, which have been separatelyproduced, by different administration routes in a staggered manner(e.g., administration in the order of the compound of the presentinvention and the combination drug, or in the reverse order).

The dose of the combination drug can be appropriately determined withthe clinically-used dose as the standard. In addition, the mixing ratioof compound of the present invention and the combination drug can beappropriately determined according to the administration subject,administration route, target disease, symptom, combination and the like.For example, when the administration subject is human, 0.01 to 100 partsby weight of the combination drug can be used per 1 part by weight ofthe compound of the present invention.

The compound can be used in combination with a means for providing thepatients with an additional or synergistic effect, for example, use ofextracorporeal rheopheresis, use of a transplantable compact telescope,laser photocoagulation of drusen, a microstimulation therapy and thelike.

Examples of the above-mentioned “therapeutic agent for diabetes” includeinsulin preparations (e.g., animal insulin preparations extracted frompancreas of bovine or swine; human insulin preparations geneticallysynthesized using Escherichia coli or yeast; zinc insulin; protaminezinc insulin; fragment or derivative of insulin (e.g., INS-1), oralinsulin preparation), insulin sensitizers (e.g., pioglitazone or a saltthereof (preferably hydrochloride), rosiglitazone or a salt thereof(preferably maleate), Netoglitazone (MCC-555), Rivoglitazone (CS-011),FK-614, compound described in WO 01/38325, Tesaglitazar (AZ-242),Ragaglitazar (NN-622), Muraglitazar (BMS-298585), Edaglitazone(BM-13-1258), Metaglidasen (MBX-102), Naveglitazar (LY-519818), MX-6054,LY-510929, AMG131 (T-131) or a salt thereof, THR-0921), α-glucosidaseinhibitors (e.g., voglibose, acarbose, miglitol, emiglitate), biguanides(e.g., phenformin, metformin, buformin or a salt thereof (e.g.,hydrochloride, fumarate, succinate)), insulin secretagogues[sulfonylurea (e.g., tolbutamide, glibenclamide, gliclazide,chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride,glipizide, glybuzole), repaglinide, nateglinide, mitiglinide or calciumsalt hydrate thereof], dipeptidyl peptidase IV inhibitors (e.g.,Vildagliptin (LAF237), P32/98, Sitagliptin (MK-431), alogliptin,Trelagliptin, P93/01, PT-100, Saxagliptin (BMS-477118), BI1356, GRC8200,MP-513, PF-00734200, PHX1149, SK-0403, ALS2-0426, T-6666, TS-021,KRP-104), β3 agonists (e.g., AJ=9677), GPR40 agonist, GLP-1 receptoragonists [e.g., GLP-1, GLP-1MR agent, NN-2211, AC-2993 (exendin-4)),BIM-51077, Aib(8,35)hGLP-1(7,37)NH2, CJC-1131], amylin agonists (e.g.,pramlintide), phosphotyrosine phosphatase inhibitors (e.g., sodiumvanadate), gluconeogenesis inhibitors (e.g., glycogen phosphorylaseinhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists),SGLUT (sodium-glucose cotransporter) inhibitors (e.g., T-1095,dapagliflozin, remogliflozin), 1β-hydroxysteroid dehydrogenaseinhibitors (e.g., BVT-3498), adiponectin or agonist thereof, IKKinhibitors (e.g., AS-2868), leptin resistance improving drugs,somatostatin receptor agonists (e.g., compounds described in WO01/25228, WO 03/42204, WO 98/44921, WO 98/45285, WO 99/22735 etc.),glucokinase activators (e.g., Ro-28-1675), and ACC2 (acetyl-CoAcarboxylase 2) inhibitor.

Examples of the “therapeutic agents for diabetic complications” includealdose reductase inhibitors (e.g., Tolrestat, Epalrestat, zenarestat,Zopolrestat, minalrestat, Fidarestat, CT-112, ranirestat (AS-3201)),neurotrophic factors and increasing drugs thereof (e.g., NGF, NT-3,BDNF, neurotrophin production-secretion promoters described inWO01/14372 (e.g.,4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole)),PKC inhibitors (e.g., ruboxistaurin mesylate), AGE inhibitors (e.g.,ALT946, pimagedine, N-phenacylthiazolium bromide (ALT766), EXO-226,Pyridorin, Pyridoxamine), active oxygen scavengers (e.g., thiocticacid), cerebral vasodilators (e.g., tiapuride, mexiletine), somatostatinreceptor agonists (BIM23190), and apoptosis signal regulating kinase-1(ASK-1) inhibitors.

Examples of the “hyperlipidemia therapeutic agent” include statincompounds as cholesterol synthesis inhibitors (e.g., cerivastatin,pravastatin, simvastatin, lovastatin, rosuvastatin, atorvastatin,fluvastatin, pitavastatin or salts thereof (e.g., sodium salt, etc.)etc.), squalene synthetase inhibitors or fibrate compounds withhypotriglyceride action (e.g., bezafibrate, clofibrate, simfibrate,clinofibrate, etc.), cholesterol absorption inhibitors (e.g., zetia),anion-exchange resins (e.g., cholestyramine), probucol, nicotinic drugs(e.g., nicomol, niceritrol), phytosterols (e.g., soysterol,γ-oryzanol)), fish oil preparations (e.g., EPA, DHA, omacor), PPARα-agonist, PPAR γ-agonist, PPAR δ-agonist, LXR agonist, FXR antagonist,FXR agonist, DGAT inhibitor, MGAT inhibitor, MTP inhibitor (e.g.,lomitapide), and nucleic acid drugs containing ApoB antisense (e.g.,mipomersen) or PCSK9 siRNA antisense oligonucleotide.

Examples of the antihypertensive agent include angiotensin convertingenzyme inhibitors (e.g., captopril, enalapril, delapril and the like),angiotensin II antagonists (e.g., candesartan cilexetil, candesartan,azilsartan, azilsartan medoxomil, losartan, losartan potassium,eprosartan, valsartan, telmisartan, irbesartan, tasosartan, olmesartan,olmesartan medoxomil etc.), calcium antagonist (e.g., manidipine,nifedipine, amlodipine, efonidipine, nicardipine etc.), 3-blocker (e.g.,propranolol, nadolol, timolol, nipradilol, bunitrolol, indenolol,Penbutolol, carteolol, carvedilol, pindolol, acebutolol, atenolol,bisoprolol, metoprolol, labetalol, amosulalol, arotinolol etc.), andclonidine.

Examples of the “antiobesity agent” include monoamine uptake inhibitors(e.g., phentermine, sibutramine, mazindol, fluoxetine, tesofensine),serotonin 2C receptor agonists (e.g., s15 lorcaserin), serotonin 6receptor antagonists, histamine H3 receptor, GABA modulator (e.g.,topiramate), neuropeptide Y antagonists (e.g., velneperit), cannabinoidreceptor antagonists (e.g., rimonabant, taranabant), ghrelinantagonists, ghrelin receptor antagonists, ghrelin acylation enzymeinhibitors, opioid receptor antagonists (e.g., GSK-1521498), orexinreceptor antagonists, melanocortin 4 receptor agonists,11β-hydroxysteroid dehydrogenase inhibitors (e.g., AZD-4017), pancreaticlipase inhibitors (e.g., orlistat, cetilistat), β3 agonists (e.g.,N-5984), diacylglycerol acyltransferase 1 (DGAT1) inhibitors, acetylCoAcarboxylase (ACC) inhibitors, stearate CoA desaturase inhibitors,microsomal triglyceride transfer protein inhibitors (e.g., R-256918),Na-glucose cotransporter inhibitors (e.g., JNJ=28431754, remogliflozin),NFK inhibitors (e.g., HE-3286), PPAR agonists (e.g., GFT-505,DRF-11605), phosphotyrosine phosphatase inhibitors (e.g., sodiumvanadate, Trodusquemin), GPR119 agonists (e.g., PSN-821), glucokinaseactivators (e.g., AZD-1656), leptin, leptin derivatives (e.g.,metreleptin), CNTF (ciliary neurotrophic factor), BDNF (brain-derivedneurotrophic factor), cholecystokinin agonists, glucagon-like peptide-1(GLP-1) preparations (e.g., animal GLP-1 preparations extracted from thepancreas of bovine or swine; human preparations genetically synthesizedusing Escherichia coli or yeast; fragments or derivatives of GLP-1(e.g., exenatide, liraglutide)), amylin preparations (e.g., pramlintide,AC-2307), neuropeptide Y agonists (e.g., PYY3-36, derivatives ofPYY3-36, obineptide, TM-30339, TM-30335), oxyntomodulin preparations:FGF21 preparations (e.g., animal FGF21 preparations extracted from thepancreas of bovine or swine; human FGF21 preparations geneticallysynthesized using Escherichia coli or yeast; fragments or derivatives ofFGF21), and anorexigenic agents (e.g., P-57).

Examples of the “diuretics” include xanthine derivatives (e.g., sodiumsalicylate and theobromine, calcium salicylate and theobromine),thiazide preparations (e.g., ethiazide, cyclopenthiazide,trichloromethiazide, hydrochlorothiazide, hydroflumethiazide,benzylhydrochlorothiazide, penflutizide, poly5thiazide,methyclothiazide), antialdosterone preparations (e.g., spironolactone,eplerenone, triamterene), carbonate dehydratase inhibitors (e.g.,acetazolamide), chlorobenzenesulfonamide preparations (e.g.,chlortalidone, mefruside, indapamide), azosemide, isosorbide, etacrynicacid, piretanide, bumetanide, and furosemide.

Examples of the therapeutic agent for macular degeneration includefenretinide (4-hydroxy(phenyl)retinamide), compound described in WO2009/042444, negatively-charged phospholipid, particular mineral (e.g.,copper-containing mineral such as copper oxide and the like, andzinc-containing mineral such as zinc oxide and the like,selenium-containing compound).

Examples of the antioxidant include vitamin C, vitamin E, β-carotene andother carotenoid, coenzyme Q,4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (also known as Tempol),lutein, butylated hydroxytoluene, resveratrol, trolox analogue(PNU-83836-E), and bilberry extract.

Examples of the nitric oxide inducing agent include L-arginine,L-homoarginine and N-hydroxy-L-arginine (e.g., nitrosated L-arginine,nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine, nitrosylatedN-hydroxy-L-arginine, nitrosated L-homoarginine, nitrosylatedL-homoarginine), L-arginine precursor and/or physiologically acceptablesalt thereof (e.g., citrulline, ornithine, glutamine, lysine),polypeptide containing at least one of the above-mentioned amino acids,enzyme arginase inhibitor (e.g., N-hydroxy-L-arginine and2(S)-amino-6-boronohexanoic acid), and substrate for nitric oxide orclosely-related derivative thereof.

Examples of the matrix metalloproteinase (MMPs) inhibitor include tissueinhibitors of metalloproteinase (TIMPs) (e.g., TIMP-1, TIMP-2, TIMP-3,TIMP-4), a2-macroglobulin, tetracycline (e.g., tetracycline,minocycline, doxycycline), hydroxamate (e.g., batimastat, MARIMISTAT,TROCADE), chelating agent (e.g., EDTA, cysteine, acetylcysteine,D-penicillamine, gold salt), synthetic MMP fragment,succinylmercaptopurine, phosphoramidate, and hydroxamic acid(hydroxaminic acid).

Examples of the anti-angiogenesis agent or anti-VEGF agent includeRhufab V2 (Lucentis), tryptophanyl-tRNA synthetase (TrpRS), Eye 001(anti-VERG pegylated aptamer), squalamine, Retaane 15 mg (anecortaveacetate for depot suspended product; Alcon, Inc.), Combretastain A4prodrug (CA4P), Macugen, Mifeprex (mifepristone-ru486), sub-tenontriamcinolone acetonide, intravitreal crystalline triamcinoloneacetonide, prinomastat (AG3340), fluocinolone acetonide (includingfluocinolone intraocular implant), VEGFR inhibitor, and VEGF-trap.

Examples of the chemotherapeutic agents include alkylating agents (e.g.,cyclophosphamide, ifosfamide), metabolic antagonists (e.g.,methotrexate, 5-fluorouracil and derivative thereof), antitumorantibiotics (e.g., mitomycin, Adriamycin, etc.), plant-derived antitumoragents (e.g., vincristine, vindesine, Taxol), cisplatin, carboplatin,etoposide and the like. Of these, Furtulon or NeoFurtulon, which are5-fluorouracil derivatives, and the like are preferable.

Examples of the above-mentioned “immunotherapeutic agents” includemicroorganism or bacterial components (e.g., muramyl dipeptidederivatives, Picibanil, etc.), polysaccharides having immunitypotentiating activity (e.g., lentinan, schizophyllan, krestin, etc.),cytokines obtained by genetic engineering techniques (e.g., interferon,interleukin (IL), etc.), colony stimulating factors (e.g., granulocytecolony stimulating factor, erythropoietin, etc.) and the like, withpreference given to interleukins such as IL-1, IL-2, IL-12 and the like.

Examples of the antithrombotic agent include heparin (e.g., heparinsodium, heparin calcium, dalteparin sodium), warfarin (e.g., warfarinpotassium), anti-thrombin drug (e.g., aragatroban, dabigatran),thrombolytic agent (e.g., urokinase), tisokinase, alteplase, nateplase,monteplase, pamiteplase), platelet aggregation inhibitor (e.g.,ticlopidine hydrochloride, cilostazol), ethyl icosapentate, beraprostsodium, sarpogrelate hydrochloride, prasugrel, E5555, SHC530348), FXainhibitor (e.g.,1-(1-{(2S)-3-[(6-chloronaphthalen-2-yl)sulfonyl]-2-hydroxypropanoyl}piperidin-4-yl)tetrahydropyrimidin-2(1H)-one,rivaroxaban, apixaban, DU-156, YM150).

Examples of the “therapeutic agents for osteoporosis” includealfacalcidol, calcitriol, elcaltonin, calcitonin salmon, estriol,ipriflavone, pamidronate disodium, alendronate sodium hydrate, andincadronate disodium.

Examples of the “antidementia agent” include tacrine, donepezil,rivastigmine, and galanthamine.

Examples of the erectile dysfunction improving drug include apomorphine,sildenafil citrate.

Examples of the therapeutic agents for urinary incontinence orpollakiuria include flavoxate hydrochloride, oxybutynin hydrochloride,propiverine hydrochloride.

Examples of the therapeutic agents for dysuria include acetylcholineesterase inhibitors (e.g., distigmine).

In addition, examples of the combination drug includes drugs having acachexia-improving action established in animal models and clinicalsituations, such as cyclooxygenase inhibitors (e.g., indomethacin),progesterone derivatives (e.g., megestrol acetate), glucosteroids (e.g.,dexamethasone), metoclopramide agents, tetrahydrocannabinol agents, fatmetabolism improving agents (e.g., eicosapentanoic acid), growthhormones, IGF-1, or antibodies to a cachexia-inducing factor such asTNF-α, LIF, IL-6, oncostatin M.

Furthermore, examples of the combination drug includes nerveregeneration promoting drugs (e.g., Y-128, VX-853, prosaptide),antidepressant (e.g., desipramine, amitriptyline, imipramine),antiepileptic (e.g., lamotrigine), antiarrhythmic drugs (e.g.,mexiletine), acetylcholine receptor ligand (e.g., ABT-594), endothelinreceptor antagonist (e.g., ABT-627), monoamine uptake inhibitors (e.g.,tramadol), narcotic analgesics (e.g., morphine), GABA receptor agonist(e.g., gabapentin), α2 receptor agonist (e.g., clonidine), topicalanalgesic (e.g., capsaicin), antianxiety drug (e.g., benzodiazepine),dopamine agonist (e.g., apomorphine), midazolam, ketoconazole and thelike.

EXAMPLES

The present invention is explained in detail in the following byreferring to Examples, Experimental Examples and Formulation Examples.However, the examples do not limit the present invention and the presentinvention can be modified within the scope of the present invention.

The “room temperature” in the following Examples is generally about 10°C. to about 35° C. The ratio for a mixed solvent is, unless otherwisespecified, a volume mixing ratio and % means wt % unless otherwisespecified.

In silica gel column chromatography, the indication of NH means use ofaminopropylsilane-bonded silica gel and the indication of Diol means useof 3-(2,3-dihydroxypropoxy)propylsilane bond silica gel. In HPLC (highperformance liquid chromatography), the indication of C18 means use ofoctadecyl-bonded silica gel. The ratio of elution solvents is, unlessotherwise specified, a volume mixing ratio.

In the following Examples, the following abbreviations are used.

-   mp: melting point-   MS: mass spectrum-   M: molar concentration-   CDCl₃: deuterated chloroform-   DMSO: dimethyl sulfoxide-   DMSO-d6: deuterated dimethyl sulfoxide-   ¹H NMR: proton nuclear magnetic resonance-   LC/MS: liquid chromatography mass spectrometer-   ESI: electrospray ionization-   APCI: atmospheric pressure chemical ionization-   DME: 1,2-dimethoxyethane-   DMA: N,N-dimethylacetamide-   HATU: 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium-   hexafluorophosphate-   HOBt: 1-hydroxybenzotriazole-   THF: tetrahydrofuran-   DMF: N,N-dimethylformamide-   TFA: trifluoroacetic acid-   LHMDS: hexamethyldisilazane lithium-   n-: normal-   s-: secondary-   t-: tertiary

¹H NMR was measured by Fourier-transform type NMR. For the analysis,ACD/SpecManager (trade name) and the like were used. Very mild peaks ofprotons of hydroxyl group, amino group and the like are not described.

MS was measured by LC/MS. As the ionization method, ESI method, or APCImethod was used. The data indicates those found. Generally, molecularion peak ([M+H]⁺, [M−H]⁻ and the like) is observed; however, when thecompound has a tert-butoxycarbonyl group, a peak after elimination of atert-butoxycarbonyl group or tert-butyl group may be observed as afragment ion. When the compound has a hydroxyl group, a peak afterelimination of H₂O may be observed as a fragment ion. In the case of asalt, a molecular ion peak or fragment ion peak of free form isgenerally observed.

The unit of sample concentration (c) in optical rotation ([α]_(D)) isg/100 mL.

The elemental analytical value (Anal.) shows Calculated value (Calcd)and Found value (Found).

Example 1 ((2-(3,5-bis(trifluoromethyl)phenyl)pyrimidin-5-yl)oxy)aceticacid A) tert-butyl 2-((2-chloropyrimidin-5-yl)oxy)acetate

To a mixture of 2-chloropyrimidin-5-ol (5.7 g), tert-butyl2-bromoacetate (9.80 g) and DMF (75 mL) was added potassium phosphate(14.83 g) at room temperature, and the mixture was stirred at 50° C. for2 hr. The reaction mixture was quenched with water at room temperature,and extracted with ethyl acetate. The extract was washed with water andsaturated brine, dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (10.57 g).

MS: [M+H]⁺ 245.0.

B) tert-butyl2-((2-(3,5-bis(trifluoromethyl)phenyl)pyrimidin-5-yl)oxy)acetate

To a mixture of tert-butyl 2-((2-chloropyrimidin-5-yl)oxy)acetate (10.5g), (3,5-bis(trifluoromethyl)phenyl)boronic acid (16.60 g), potassiumcarbonate (11.86 g), water (30 mL) and DME (150 mL) was addedtetrakis(triphenylphosphine)palladium (0) (2.479 g) at room temperature,and the mixture was stirred under a nitrogen atmosphere at 100° C. for10 hr. The reaction mixture was diluted with water at room temperature,and extracted with ethyl acetate. The extract was washed with water andsaturated brine, dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (NH, ethyl acetate/hexane) to give the titlecompound (7.35 g).

MS: [M+H]⁺ 423.1.

C) ((2-(3,5-bis(trifluoromethyl)phenyl)pyrimidin-5-yl)oxy)acetic acid

To tert-butyl2-((2-(3,5-bis(trifluoromethyl)phenyl)pyrimidin-5-yl)oxy)acetate (7.3 g)was added TFA (25 mL) at 0° C., and the mixture was stirred at roomtemperature for 3 hr. The solvent was evaporated from the reactionmixture under reduced pressure. The obtained solid was recrystallizedfrom ethyl acetate/hexane to give the title compound (5.5 g).

¹H NMR (300 MHz, DMSO-d₆) δ 5.01 (2H, s), 8.26 (1H, s), 8.76 (2H, s),8.82 (2H, s), 13.34 (1H, brs).

Example 2 ((6-(3,5-bis(trifluoromethyl)phenyl)pyridin-3-yl)oxy)aceticacid A) 6-(3,5-bis(trifluoromethyl)phenyl)pyridin-3-ol

To a mixture of 6-bromopyridin-3-ol (32 g),(3,5-bis(trifluoromethyl)phenyl)boronic acid (61.7 g), potassiumcarbonate (76 g), water (100 mL) and DME (500 mL) was addedtetrakis(triphenylphosphine)palladium (0) (8.50 g) under a nitrogenatmosphere at room temperature, and the mixture was stirred under anitrogen atmosphere at 100° C. for 10 hr. To the reaction mixture wasadded 2N hydrochloric acid (555 mL) at 0° C., and the mixture wasextracted with ethyl acetate. The extract was washed with water andsaturated brine, dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (50 g).

MS: [M+H]⁺ 308.0.

B) tert-butyl2-((6-(3,5-bis(trifluoromethyl)phenyl)pyridin-3-yl)oxy)acetate

To a mixture of 6-(3,5-bis(trifluoromethyl)phenyl)pyridin-3-ol (40 g),tert-butyl 2-bromoacetate (30.5 g) and DMF (100 mL) was added potassiumcarbonate (36.0 g) at room temperature, and the mixture was stirred atroom temperature overnight. The reaction mixture was quenched with waterat room temperature, and extracted with ethyl acetate. The extract waswashed with water and saturated brine, dried over magnesium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (NH, ethyl acetate/hexane)to give the title compound (47.8 g).

MS: [M+H]⁺ 422.1.

C) ((6-(3,5-bis(trifluoromethyl)phenyl)pyridin-3-yl)oxy)acetic acid

To a mixture of tert-butyl2-((6-(3,5-bis(trifluoromethyl)phenyl)pyridin-3-yl)oxy)acetate (0.999g), THF (5 mL) and ethanol (10 mL) was added 1N aqueous sodium hydroxidesolution (10 mL) at 0° C., and the mixture was stirred at roomtemperature for 1.5 hr. To the reaction mixture was added dropwise at 0°C. 1N hydrochloric acid (10 mL), and the mixture was stirred at roomtemperature for 1 hr. The resulting solid was collected by filtration,washed with water, and dried under reduced pressure. The obtained solidwas dissolved in ethanol (8.0 mL)/water (0.9 mL) at 75° C., water (7.6mL) was added dropwise at 75° C., and the mixture was stirred at 75° C.for 0.5 hr, and the mixture was stirred at room temperature overnight.The obtained solid was collected by filtration, washed withethanol/water (=1/1) and water, and dried under reduced pressure to givethe title compound (0.7758 g).

¹H NMR (300 MHz, DMSO-d₆) δ 4.88 (2H, s), 7.55 (1H, dd, J=9.1, 3.0 Hz),8.11 (1H, s), 8.27 (1H, d, J=9.1 Hz), 8.46 (1H, d, J=2.6 Hz), 8.68 (2H,s), 13.20 (1H, brs).

Example 33-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)propanoic acid A)(E)-1-(3,5-bis(trifluoromethyl)phenyl)-3-(dimethylamino) prop-2-en-1-one

A mixture of 1-(3,5-bis(trifluoromethyl)phenyl) ethanone (100 g) andN,N-dimethylformamide dimethyl acetal (259 mL) was stirred at 100° C.for 2 hr. After completion of the reaction, the reaction mixture wascooled to room temperature, and poured into ice water. The resultingsolid was collected by filtration, washed with ice-cold water andpetroleum ether, and dried under reduced pressure to give the titlecompound (200 g). MS: [M+H]⁺ 312.2.

B) 3-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazole

To a mixture of(E)-1-(3,5-bis(trifluoromethyl)phenyl)-3-(dimethylamino)prop-2-en-1-one(100 g) and acetic acid (1000 mL) was added hydrazine monohydrate (40.2g) at room temperature, and the mixture was stirred at 100° C. for 2 hr.After completion of the reaction, the reaction mixture was cooled toroom temperature, and poured into ice water. The resulting solid wascollected by filtration, and washed with cold water. The obtained solidwas dissolved in ethyl acetate, and washed with water and saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure to give the title compound (70 g).

MS: [M+H]⁺ 281.1.

C) 3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)propanenitrile

To a mixture of 3-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazole (140 g)and DMF (1680 mL) was added cesium carbonate (243.7 g) at 0° C., then3-bromopropionitrile (83.73 g) was added 0° C., and the mixture wasstirred at 70° C. for 2 hr. After completion of the reaction, thereaction mixture was cooled to room temperature, and poured into icewater. The resulting solid was collected by filtration, and washed withwater. The obtained solid was dissolved in ethyl acetate, washed withsaturated brine and water, dried over anhydrous sodium sulfate, andevaporated under reduced pressure. To the obtained solid was addeddiethyl ether, and the mixture was stirred for 20 min and filtered togive the title compound (113.2 g).

MS: [M+H]⁺ 334.2.

D) 3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)propanoic acid

To 6N hydrochloric acid (150 mL) was added3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)propanenitrile(2.8 g) at room temperature, and the mixture was stirred at 100° C. for5 hr. The reaction mixture was diluted with water at room temperature,and the mixture was extracted with ethyl acetate. The extract was washedwith water and saturated brine, dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained solid wasrecrystallized from ethyl acetate/hexane to give the title compound(2.60 g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.87 (2H, t, J=6.8 Hz), 4.40 (2H, t, J=6.8Hz), 7.07 (1H, d, J=2.3 Hz), 7.87 (1H, d, J=2.3 Hz), 8.00 (1H, s), 8.40(2H, s), 12.43 (1H, s).

Example 4((4-(3,5-bis(trifluoromethyl)phenyl)-1,3-oxazol-2-yl)oxy)acetic acid A)1-(3,5-bis(trifluoromethyl)phenyl)-2-bromoethanone

A mixture of 3′,5′-bis(trifluoromethyl)acetophenone (100 g) and aceticacid (400 mL) was heated to 90° C., a catalytic amount of bromine wasadded, and the oil bath was removed. The remaining bromine (20 mL) wasadded, and the mixture was stirred at room temperature for 1 hr. Aftercompletion of the reaction, the reaction mixture was diluted with icewater. The resulting solid was collected by filtration, washed withice-cold water, and dried under reduced pressure to give the titlecompound (110 g).

¹H NMR (300 MHz, CDCl₃) δ 4.46 (2H, d, J=1.4 Hz), 8.12 (1H, s), 8.43(2H, s).

B) 1-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethanone

To a mixture of 1-(3,5-bis(trifluoromethyl)phenyl)-2-bromoethanone (90g) and methanol (450 mL) was added sodium formate (91.34 g) at 0° C.,and the mixture was stirred at 50 to 55° C. for 6 hr. The reactionmixture was concentrated, diluted with ethyl acetate, filtered to removethe resulting solid, and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/petroleum ether) to give the title compound (35 g).

MS: [M−H]⁺ 271.2.

C) 2-(3,5-bis(trifluoromethyl)phenyl)-2-oxoethyl phenyl carbonate

To a mixture of 1-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethanone (35g) and THF (350 mL) was added pyridine (15.68 mL) at 0° C., phenylchloroformate (30.4 g) was added at 0° C., and the mixture was stirredat room temperature until the reaction was completed. After completionof the reaction, the reaction mixture was diluted with ethyl acetateunder a nitrogen atmosphere, and the solid was filtered and washed withethyl acetate. The filtrate was concentrated under reduced pressure togive the title compound (45 g).

MS: [M+H]⁺ 393.2.

D) 4-(3,5-bis(trifluoromethyl)phenyl)oxazol-2 (3H)-one

To a mixture of 2-(3,5-bis(trifluoromethyl)phenyl)-2-oxoethyl phenylcarbonate (45 g) and acetic acid (450 mL) was added ammonium acetate(34.7 g) at room temperature, and the mixture was stirred at 140° C. for1 hr. After completion of the reaction, the reaction mixture was dilutedwith ice water, and extracted with ethyl acetate. The extract was washedwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/petroleum ether) togive the title compound (14 g).

MS: [M+H]⁺ 298.2.

E) 4-(3,5-bis(trifluoromethyl)phenyl)-2-chlorooxazole

To a mixture of 4-(3,5-bis(trifluoromethyl)phenyl)oxazol-2(3H)-one (27g) and phosphoryl chloride (37.48 mL) was added N,N-diethylaniline(13.56 g) at room temperature, and the mixture was stirred at 100° C.overnight. After completion of the reaction, the reaction mixture wasdiluted with ice water, and extracted with ethyl acetate. The extractwas washed with saturated brine and water and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/petroleum ether) to give the titlecompound (20 g).

¹H NMR (400 MHz, CDCl₃) δ 7.85 (1H, s), 8.07 (1H, s), 8.14 (2H, s).

F) tert-butyl 2-((4-(3,5-bis(trifluoromethyl)phenyl)oxazol-2-yl)oxy)acetate

To a mixture of sodium hydride (5.07 g, 60% in oil) and THF (50 mL) wasadded a mixture of tert-butyl 2-hydroxyacetate (8.368 g) and THF (50 mL)at 0° C. Then, a mixture of4-(3,5-bis(trifluoromethyl)phenyl)-2-chlorooxazole (20 g) and THF (100mL) was added at 0° C., and the mixture was stirred at room temperaturefor 1 hr. After completion of the reaction, the reaction mixture wasdiluted with ice water, and extracted with ethyl acetate. The extractwas washed with saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure. The residuewas purified by silica gel column chromatography (ethylacetate/petroleum ether) to give the title compound (18.2 g).

MS: [M+H]⁺ 412.1.

G) ((4-(3,5-bis(trifluoromethyl)phenyl)-1,3-oxazol-2-yl)oxy)acetic acid

To a mixture of tert-butyl2-((4-(3,5-bis(trifluoromethyl)phenyl)oxazol-2-yl)oxy)acetate (0.2 g),THF (1.0 mL) and methanol (1.0 mL) was added 2N aqueous sodium hydroxidesolution (1.0 mL) at room temperature, and the mixture was stirred atroom temperature for 1.5 hr. To the reaction mixture was added 1Nhydrochloric acid (2.0 mL) at room temperature, and the mixture waspoured into saturated brine, and extracted with ethyl acetate. Theextract was dried over anhydrous sodium sulfate and the solvent wasevaporated under reduced pressure. The obtained solid was diluted withethyl acetate (0.2 mL) and heated to 50° C. Heptane (1.0 mL) was addeddropwise at 50° C., and the mixture was stirred at 50° C. for 0.5 hr,and at room temperature overnight. The obtained solid was collected byfiltration, washed with ethyl acetate/heptane (=1/10) and heptane, anddried under reduced pressure to give the title compound (0.12 g).

¹H NMR (300 MHz, DMSO-d₆) δ 5.04 (2H, s), 8.06 (1H, s), 8.32 (2H, s),8.61 (1H, s), 13.42 (1H, brs).

Example 5((1-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)oxy)acetic acid A)(3,5-bis(trifluoromethyl)phenyl)hydrazine

A mixture of (3,5-bis(trifluoromethyl)phenyl)hydrazine hydrochloride(300 g), water (1500 mL) and ethyl acetate (1500 mL) was cooled to 10 to15° C., basified by adding sodium hydroxide (70 g), and the mixture wasstirred at room temperature for 0.5 hr. After completion of thereaction, the reaction mixture was extracted with ethyl acetate. Theextract was washed with saturated brine and water, dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure togive the title compound (200.2 g).

MS: [M+H]⁺ 245.0.

B) 1-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazol-3-ol

A mixture of (3,5-bis(trifluoromethyl)phenyl)hydrazine (100 g) andtert-butanol (1000 mL) was stirred at 30° C., and ethyl propiolate(46.25 g) was added. After cooling to 0° C., potassium tert-butoxide (92g) was gradually added, and the mixture was stirred at room temperaturefor 48 hr. After completion of the reaction, the reaction mixture wasquenched with ice water, ethyl acetate was added, and the mixture wasstirred at room temperature for 20 min and extracted with ethyl acetate.The extract was washed with water and saturated brine, dried overanhydrous sodium sulfate and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/petroleum ether) to give the title compound (64.2 g).

MS: [M+H]⁺ 297.1.

C) tert-butyl2-((1-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)oxy)acetate

To a mixture of 1-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazol-3-ol (128g) and DMF (2400 mL) was added potassium carbonate (119.35 g) at 0° C.,and then tert-butyl 2-bromoacetate (92.78 g) was added, and the mixturewas stirred at room temperature for 0.5 hr. After completion of thereaction, the reaction mixture was poured into ice water. The resultingsolid was collected by filtration, washed with n-pentane, and atreatment with activated carbon and slurry wash with petroleum etherwere performed to give the title compound (108.6 g).

MS: [M+H]⁺ 411.1.

D) ((1-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)oxy)acetic acid

To a mixture of tert-butyl2-((1-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)oxy)acetate (0.2g), THF (2.0 mL) and methanol (1.0 mL) was added 2N aqueous sodiumhydroxide solution (1.0 mL) at room temperature, and the mixture wasstirred at room temperature for 1.5 hr. To the reaction mixture wasadded 1N hydrochloric acid (2.0 mL) at room temperature, and the mixturewas poured into saturated brine, and extracted with ethyl acetate. Theextract was dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. The obtained solid was diluted withethyl acetate (0.3 mL) and heated to 50° C. Heptane (1.5 mL) was addeddropwise at 50° C., and the mixture was stirred at 50° C. for 0.5 hr andat room temperature overnight. The obtained solid was collected byfiltration, washed with ethyl acetate/heptane (=1/10) and heptane, anddried under reduced pressure to give the title compound (0.137 g).

¹H NMR (300 MHz, DMSO-d₆) δ 4.78 (2H, s), 6.21 (1H, d, J=2.6 Hz), 7.92(1H, s), 8.35 (2H, s), 8.71 (1H, d, J=2.6 Hz), 13.12 (1H, s).

Example 6 Ethyl2-((2-(3,5-bis(trifluoromethyl)phenyl)pyrimidin-5-yl)oxy)acetate A)tert-butyl 2-((2-chloropyrimidin-5-yl)oxy)acetate

To a mixture of 2-chloropyrimidin-5-ol (5.7 g), tert-butyl2-bromoacetate (9.80 g) and DMF (75 mL) was added potassium phosphate(14.83 g) at room temperature, and the mixture was stirred at 50° C. for2 hr. The reaction mixture was quenched with water at room temperature,and extracted with ethyl acetate. The extract was washed with water andsaturated brine, dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (10.57 g).

MS: [M+H]⁺ 245.0.

B) tert-butyl2-((2-(3,5-bis(trifluoromethyl)phenyl)pyrimidin-5-yl)oxy)acetate

To a mixture of tert-butyl 2-((2-chloropyrimidin-5-yl)oxy)acetate (10.5g), (3,5-bis(trifluoromethyl)phenyl)boronic acid (16.60 g), potassiumcarbonate (11.86 g), water (30 mL) and DME (150 mL) was addedtetrakis(triphenylphosphine)palladium (0) (2.479 g) at room temperature,and the mixture was stirred under a nitrogen atmosphere at 100° C. for10 hr. The reaction mixture was diluted with water at room temperature,and extracted with ethyl acetate. The extract was washed with water andsaturated brine, dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (NH, ethyl acetate/hexane) to give the titlecompound (7.35 g).

MS: [M+H]⁺ 423.1.

C) ((2-(3,5-bis(trifluoromethyl)phenyl)pyrimidin-5-yl)oxy)acetic acid

To tert-butyl2-((2-(3,5-bis(trifluoromethyl)phenyl)pyrimidin-5-yl)oxy)acetate (7.3 g)was added TFA (25 mL) at 0° C., and the mixture was stirred at roomtemperature for 3 hr. Under reduced pressure, the solvent was evaporatedfrom the reaction mixture. The obtained solid was recrystallized fromethyl acetate/hexane to give the title compound (5.5 g).

¹H NMR (300 MHz, DMSO-d₆) δ 5.01 (2H, s), 8.26 (1H, s), 8.76 (2H, s),8.82 (2H, s), 13.34 (1H, brs).

D) ethyl2-((2-(3,5-bis(trifluoromethyl)phenyl)pyrimidin-5-yl)oxy)acetate

To a mixture of((2-(3,5-bis(trifluoromethyl)phenyl)pyrimidin-5-yl)oxy)acetic acid (100mg) and ethanol (2.0 mL) was added concentrated sulfuric acid (2 μL) atroom temperature, and the mixture was heated under reflux for 8 hr. Thereaction mixture was diluted with ethyl acetate, added to saturatedaqueous sodium hydrogen carbonate solution at room temperature, and themixture was extracted with ethyl acetate. The extract was washed withwater and saturated brine, dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure to give the title compound(104 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.34 (3H, t, J=7.2 Hz), 4.32 (2H, q, J=7.2Hz), 4.78 (2H, s), 7.94 (1H, s), 8.53 (2H, s), 8.87 (2H, s).

Example 7 methyl2-((6-(3,5-bis(trifluoromethyl)phenyl)pyridin-3-yl)oxy)acetate A)6-(3,5-bis(trifluoromethyl)phenyl)pyridin-3-ol

To a mixture of 6-bromopyridin-3-ol (32 g),(3,5-bis(trifluoromethyl)phenyl)boronic acid (61.7 g), potassiumcarbonate (76 g), water (100 mL) and DME (500 mL) was addedtetrakis(triphenylphosphine)palladium (0) (8.50 g) under a nitrogenatmosphere at room temperature, and the mixture was stirred under anitrogen atmosphere at 100° C. for 10 hr. To the reaction mixture wasadded at 0° C. 2N hydrochloric acid (555 mL), and the mixture wasextracted with ethyl acetate. The extract was washed with water andsaturated brine, dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (50 g).

MS: [M+H]⁺ 308.0.

B) methyl 2-((6-(3,5-bis(trifluoromethyl)phenyl)pyridin-3-yl)oxy)acetate

To a mixture of 6-(3,5-bis(trifluoromethyl)phenyl)pyridin-3-ol (7.31 g),methyl 2-bromoacetate (4.73 g) and DMF (75 mL) was added potassiumcarbonate (6.58 g) at room temperature, and the mixture was stirred at50° C. for 2 hr. The reaction mixture was quenched with water at roomtemperature, and extracted with ethyl acetate. The extract was washedwith water and saturated brine, dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (6.46 g).

¹H NMR (300 MHz, CDCl₃) δ 3.85 (3H, s), 4.76 (2H, s), 7.33 (1H, dd,J=8.7, 3.0 Hz), 7.77 (1H, d, J=8.3 Hz), 7.87 (1H, s), 8.41 (2H, s),8.43-8.49 (1H, m).

Example 8 Ethyl3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)propanoate A)(E)-1-(3,5-bis(trifluoromethyl)phenyl)-3-(dimethylamino)prop-2-en-1-one

A mixture of 1-(3,5-bis(trifluoromethyl)phenyl)ethanone (100 g) andN,N-dimethylformamide dimethyl acetal (259 mL) was stirred at 100° C.for 2 hr. After completion of the reaction, the reaction mixture wascooled to room temperature, and poured into ice water. The resultingsolid was collected by filtration, washed with ice-cold water andpetroleum ether, and dried under reduced pressure to give the titlecompound (200 g).

MS: [M+H]⁺ 312.2.

B) 3-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazole

To a mixture of(E)-1-(3,5-bis(trifluoromethyl)phenyl)-3-(dimethylamino)prop-2-en-1-one(100 g) and acetic acid (1000 mL) was added hydrazine monohydrate (40.2g) at room temperature, and the mixture was stirred at 100° C. for 2 hr.After completion of the reaction, the reaction mixture was cooled toroom temperature, and poured into ice water. The resulting solid wascollected by filtration, and washed with cold water. The obtained solidwas dissolved in ethyl acetate, and washed with water and saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure to give the title compound (70 g).

MS: [M+H]⁺ 281.1.

C) 3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)propanenitrile

To a mixture of 3-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazole (140 g)and DMF (1680 mL) was added cesium carbonate (243.7 g) at 0° C.,3-bromopropionitrile (83.73 g) was added at 0° C., and the mixture wasstirred at 70° C. for 2 hr. After completion of the reaction, thereaction mixture was cooled to room temperature, and poured into icewater. The resulting solid was collected by filtration, and washed withwater. The obtained solid was dissolved in ethyl acetate, and washedwith saturated brine and water, and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure. To the obtained solidwas added diethyl ether, and the mixture was stirred for 20 min andfiltered to give the title compound (113.2 g).

MS: [M+H]⁺ 334.2.

D) 3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)propanoic acid

To 6N hydrochloric acid (150 mL) was added3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)propanenitrile(2.8 g) at room temperature, and the mixture was stirred at 100° C. for5 hr. The reaction mixture was diluted with water at room temperature,and extracted with ethyl acetate. The extract was washed with water andsaturated brine, dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained solid was recrystallizedfrom ethyl acetate/hexane to give the title compound (2.60 g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.87 (2H, t, J=6.8 Hz), 4.40 (2H, t, J=6.8Hz), 7.07 (1H, d, J=2.3 Hz), 7.87 (1H, d, J=2.3 Hz), 8.00 (1H, s), 8.40(2H, s), 12.43 (1H, s).

E) ethyl3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)propanoate

To a mixture of3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)propanoic acid(301 mg) and ethanol (6.0 mL) was added concentrated sulfuric acid (3μL) at room temperature, and the mixture was heated under reflux for 19hr. The solvent was evaporated under reduced pressure, and the residuewas diluted with ethyl acetate. Saturated aqueous sodium hydrogencarbonate solution was added at room temperature, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous sodium sulfate and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (319 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.25 (3H, t, J=7.2 Hz), 2.96 (2H, t, J=6.4Hz), 4.16 (2H, q, J=7.2 Hz), 4.48 (2H, t, J=6.6 Hz), 6.60 (1H, d, J=2.6Hz), 7.53 (1H, d, J=2.3 Hz), 7.77 (1H, s), 8.21 (2H, s).

Example 9 methyl2-((4-(3,5-bis(trifluoromethyl)phenyl)-1,3-oxazol-2-yl)oxy)acetate A)1-(3,5-bis(trifluoromethyl)phenyl)-2-bromoethanone

A mixture of 3′,5′-bis(trifluoromethyl)acetophenone (100 g) and aceticacid (400 mL) was heated in an oil bath to 90° C. A catalytic amount ofbromine was added and the oil bath was removed. The remaining bromine(20 mL) was added, and the mixture was stirred at room temperature for 1hr. After completion of the reaction, the reaction mixture was dilutedwith ice water. The resulting solid was collected by filtration, washedwith ice-cold water, and dried under reduced pressure to give the titlecompound (110 g).

¹H NMR (300 MHz, CDCl₃) δ 4.46 (2H, d, J=1.4 Hz), 8.12 (1H, s), 8.43(2H, s).

B) 1-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethanone

To a mixture of 1-(3,5-bis(trifluoromethyl)phenyl)-2-bromoethanone (90g) and methanol (450 mL) was added sodium formate (91.34 g) at 0° C.,and the mixture was stirred at 50 to 55° C. for 6 hr. The reactionmixture was concentrated, diluted with ethyl acetate, and filtered toremove the resulting solid. The filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/petroleum ether) to give the title compound (35 g).

MS: [M−H]⁺ 271.2.

C) 2-(3,5-bis(trifluoromethyl)phenyl)-2-oxoethyl phenyl carbonate

To a mixture of 1-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethanone (35g) and THF (350 mL) was added pyridine (15.68 mL) at 0° C., phenylchloroformate (30.4 g) was added at 0° C., and the mixture was stirredat room temperature until the reaction was completed. After completionof the reaction, under a nitrogen atmosphere, the reaction mixture wasdiluted with ethyl acetate, and the solid was filtrated, washed withethyl acetate, and the filtrate was concentrated under reduced pressureto give the title compound (45 g).

MS: [M+H]⁺ 393.2.

D) 4-(3,5-bis(trifluoromethyl)phenyl)-1,3-oxazol-2 (3H)-one

To a mixture of 2-(3,5-bis(trifluoromethyl)phenyl)-2-oxoethyl phenylcarbonate (45 g) and acetic acid (450 mL) was added ammonium acetate(34.7 g) at room temperature, and the mixture was stirred at 140° C. for1 hr. After completion of the reaction, the reaction mixture was dilutedwith ice water, and extracted with ethyl acetate. The extract was washedwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/petroleum ether) togive the title compound (14 g).

MS: [M+H]⁺ 298.2.

E) 4-(3,5-bis(trifluoromethyl)phenyl)-2-chloro-1,3-oxazole

To a mixture of 4-(3,5-bis(trifluoromethyl)phenyl)-1,3-oxazol-2(3H)-one(27 g) and phosphoryl chloride (37.48 mL) was added N,N-diethylaniline(13.56 g) at room temperature, and the mixture was stirred at 100° C.overnight. After completion of the reaction, the reaction mixture wasdiluted with ice water, and extracted with ethyl acetate. The extractwas washed with saturated brine and water, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/petroleum ether) to give thetitle compound (20 g).

¹H NMR (400 MHz, CDCl₃) δ 7.85 (1H, s), 8.07 (1H, s), 8.14 (2H, s).

F) methyl2-((4-(3,5-bis(trifluoromethyl)phenyl)-1,3-oxazol-2-yl)oxy)acetate

To a mixture of sodium hydride (124 mg, 60% in oil) and THF (10 mL) wasadded a mixture of methyl 2-hydroxyacetate (186 mg) and THF (3 mL) at 0°C., then a mixture of4-(3,5-bis(trifluoromethyl)phenyl)-2-chloro-1,3-oxazole (650 mg) and THF(3 mL) was added at 0° C., and the mixture was stirred at roomtemperature for 1 hr. After completion of the reaction, the reactionmixture was poured into ice-cold water, and the mixture was extractedwith ethyl acetate. The extract was washed with saturated brine, driedover anhydrous sodium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/petroleum ether) to give the titlecompound (200 mg).

¹H NMR (400 MHz, CDCl₃) δ 3.85 (3H, s), 5.04 (2H, s), 7.69 (1H, s), 7.78(1H, s), 8.06 (2H, d, J=1.7 Hz).

Example 10 methyl2-((1-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)oxy)acetate A)(3,5-bis(trifluoromethyl)phenyl)hydrazine

A mixture of (3,5-bis(trifluoromethyl)phenyl)hydrazine hydrochloride(300 g), water (1500 mL) and ethyl acetate (1500 mL) was cooled to 10 to15° C., basified by adding sodium hydroxide (70 g), and the mixture wasstirred at room temperature for 0.5 hr. After completion of thereaction, the reaction mixture was extracted with ethyl acetate. Theextract was washed with saturated brine and water, dried over anhydroussodium sulfate and the solvent was evaporated under reduced pressure togive the title compound (200.2 g).

MS: [M+H]⁺ 245.0.

B) 1-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazol-3-ol

A mixture of (3,5-bis(trifluoromethyl)phenyl)hydrazine (100 g) andtert-butanol (1000 mL) was stirred at 30° C., and ethyl propiolate(46.25 g) was added. After cooling to 0° C., potassium tert-butoxide (92g) was gradually added, and the mixture was stirred at room temperaturefor 48 hr. After completion of the reaction, the reaction mixture wasquenched with ice water, ethyl acetate was added, and the mixture wasstirred at room temperature for 20 min and extracted with ethyl acetate.The extract was washed with water and saturated brine, dried overanhydrous sodium sulfate and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/petroleum ether) to give the title compound (64.2 g).

MS: [M+H]⁺ 297.1.

C) methyl2-((1-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)oxy)acetate

To a mixture of 1-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazol-3-ol (800mg) and DMF (10 mL) was added potassium carbonate (745 mg) at 0° C.,then methyl 2-bromoacetate (454 mg) was added, and the mixture wasstirred at room temperature for 0.5 hr. After completion of thereaction, the reaction mixture was poured into ice-cold water. Theresulting solid was collected by filtration, and washed with n-pentaneto give the title compound (730 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 3.71 (3H, s), 4.95 (2H, s), 6.26 (1H, d,J=2.7 Hz), 7.93 (1H, s), 8.35 (1H, d, J=1.5 Hz), 8.72 (2H, d, J=2.8 Hz).

According to the methods shown in the above-mentioned Examples or amethod analogous thereto, the Example compounds in the following Tableswere produced. The Example compounds are shown in the following Tables.In the Tables, MS shows measured values.

TABLE 1 Ex. No. IUPAC name structural formula salt MS 1((2-(3,5-bis(trifluoromethyl)- phenyl)pyrimidin-5- yl)oxy)acetic acid

364.9 2 ((6-(3,5-bis(trifluoromethyl)- phenyl)pyridin-3-yl)oxy)aceticacid

366.0 3 3-(3-(3,5- bis(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)propanoic acid

350.9 4 ((4-(3,5- bis(trifluoromethyl)phenyl)-1,3-oxazol-2-yl)oxy)acetic acid

353.8 5 ((1-(3,5- bis(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)oxy)acetic acid

352.9 6 ethyl 2-((2-(3,5- bis(trifluoromethyl)phenyl)-pyrimidin-5-yl)oxy)acetate

395.1 7 methyl 2-((6-(3,5- bis(trifluoromethyl)phenyl)-pyridin-3-yl)oxy)acetate

380.2 8 ethyl (3-(3,5- bis(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)propanoate

381.1 9 methyl 2-((4-(3,5- bis(trifluoromethyl)phenyl)-1,3-oxazol-2-yl)oxy)acetate

370.2 10  methyl 2-((1-(3,5- bis(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)oxy)acetate

369.0

Reference Example 1 Ethyl((4-(3,5-bis(trifluoromethyl)phenyl)-1,3-oxazol-2-yl)sulfanyl)acetate

To a mixture of THF (6 mL) and sodium hydride (114 mg, 60% in oil) wasadded a mixture of ethyl thioglycolate (571 mg) and THF (2 mL) at 0° C.,and the mixture was stirred for 15 min. Then, a mixture of4-(3,5-bis(trifluoromethyl)phenyl)-2-chloro-1,3-oxazole (1 g) and THF (2mL) was added at 0° C., and the mixture was stirred at room temperaturefor 1 hr. The reaction mixture was poured into ice-cooled water, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, dried over sodium sulfate and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/petroleum ether) to give thetitle compound (1 g).

MS: [M+H]⁺ 400.1.

Reference Example 2((4-(3,5-bis(trifluoromethyl)phenyl)-1,3-oxazol-2-yl)sulfanyl)aceticacid

To a mixture of ethyl((4-(3,5-bis(trifluoromethyl)phenyl)-1,3-oxazol-2-yl)sulfanyl)acetate(100 mg) and THF (2 mL) was added a mixture of lithium hydroxide (31.5mg) and water (0.5 mL) at room temperature, and the mixture was stirredat room temperature for 1 hr. The reaction mixture was concentratedunder reduced pressure, and the residue was diluted with water,acidified with concentrated hydrochloric acid at 0° C. and the mixturewas stirred for 15 min. The precipitate was collected by filtration,dried under reduced pressure, and washed with petroleum ether to givethe title compound (66 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 4.10 (2H, s), 8.07 (1H, s), 8.39 (2H, s),9.01 (1H, s).

Reference Example 3 Ethyl((6-(3,5-bis(trifluoromethyl)phenyl)pyridin-3-yl)sulfanyl)acetate A)2-(3,5-bis(trifluoromethyl)phenyl)-5-fluoropyridine

To a mixture of 2-bromo-5-fluoropyridine (1 g), toluene (10 mL) andethanol (2 mL) were added (3,5-bis(trifluoromethyl)phenyl)boronic acid(1.759 g) and potassium phosphate (1.8 g) at room temperature, and themixture was deaerated with argon for 20 min.Tetrakis(triphenylphosphine)palladium (0) (33 mg) was added at roomtemperature, and the mixture was stirred at 80° C. overnight. Thereaction mixture was filtered through celite, and the filtrate wasdiluted with water, and extracted with ethyl acetate. The extract waswashed with water and saturated brine, dried over sodium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (1.6 g).

MS: [M+H]⁺ 310.1.

B) ethyl((6-(3,5-bis(trifluoromethyl)phenyl)pyridin-3-yl)sulfanyl)acetate

To a mixture of 2-(3,5-bis(trifluoromethyl)phenyl)-5-fluoropyridine (1g), DMF (5 mL) and DMSO (5 mL) were added sodium hydrogen sulfidemonohydrate (900 mg), sodium sulfide 9 hydrate (3.88 g) anddiazabicycloundecene (1 g) at room temperature, and the mixture wasstirred at 100° C. for 12 hr. The reaction mixture was cooled to roomtemperature, tributylphosphine (50% ethyl acetate solution, 10 mL) wasadded, and the mixture was stirred at room temperature for 18 hr. Thereaction mixture was quenched with water, and extracted with ethylacetate. The extract was washed with water and saturated brine, driedover sodium sulfate and the solvent was evaporated under reducedpressure. The residue was dissolved in DMF (5 mL), potassium carbonate(535 mg) was added at room temperature, and the mixture was stirred for10 min. Ethyl 2-bromoacetate (309 mg) was added at room temperature, andthe mixture was stirred for 12 hr. The reaction mixture was quenchedwith ice water, and extracted with ethyl acetate. The extract was washedwith water and saturated brine, dried over sodium sulfate and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/petroleum ether) togive the title compound (152 mg).

MS: [M+H]⁺ 410.1.

Reference Example 4((6-(3,5-bis(trifluoromethyl)phenyl)pyridin-3-yl)sulfanyl)acetic acid

To a mixture of ethyl((6-(3,5-bis(trifluoromethyl)phenyl)pyridin-3-yl)sulfanyl)acetate (100mg), THF (2 mL) and water (0.5 mL) was added lithium hydroxidemonohydrate (30 mg) at room temperature, and the mixture was stirred atroom temperature for 2 hr. The reaction mixture was quenched with water,and concentrated under reduced pressure. The residue was diluted withwater, and washed with ethyl acetate. The aqueous layer was acidifiedwith 3 M hydrochloric acid at 0° C. The precipitate was collected byfiltration, dried under reduced pressure, and washed with pentane togive the title compound (50 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 3.97 (2H, s), 7.95 (1H, dd, J=8.3, 2.5 Hz),8.16 (1H, s), 8.28 (1H, d, J=8.8 Hz), 8.68 (1H, d, J=2.4 Hz), 8.73 (2H,s), 12.99 (1H, brs).

Reference Example 53-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)butanoic acid A)3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)butanenitrile

To a mixture of 3-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazole (300 mg)and DMF (5 mL) was added cesium carbonate (872 mg), and the mixture wascooled to 0° C. 3-Bromobutanenitrile (0.129 mL) was added at 0° C., andthe mixture was stirred at 70° C. for 2 hr. The reaction mixture waspoured into ice water at room temperature. The resulting solid wascollected by filtration, washed with water, and dried under reducedpressure to give the title compound (300 mg).

MS: [M+H]⁺ 348.2.

B) 3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)butanoic acid

To a mixture of3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)butanenitrile (300mg) and acetic acid (5 mL) was added 6N hydrochloric acid (5 mL), andthe mixture was heated under reflux for 24 hr. The reaction mixture wasconcentrated under reduced pressure, water was added to the obtainedresidue, and the mixture was extracted with ethyl acetate. The extractwas washed with water and saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by HPLC (C18, mobile phase: water/acetonitrile (0.1% HCO₂Hcontaining system)) to give the title compound (110 mg).

MS: [M+H]⁺ 367.0.

¹H NMR (400 MHz, DMSO-d₆) δ 1.49 (3H, d, J=6.8 Hz), 2.75-2.87 (1H, m),2.89-3.00 (1H, m), 4.74-4.88 (1H, m), 7.06 (1H, d, J=2.4 Hz), 7.93 (1H,d, J=2.0 Hz), 8.00 (1H, s), 8.40 (2H, s), 12.35 (1H, brs).

Reference Example 61-((3-(3,5-bis(trifluoromethyl)phenyl-1H-pyrazol-1-yl)methyl)cyclopropanecarboxylicacid A)1-((3-(3,5-bis(trifluoromethyl)phenyl-1H-pyrazol-1-yl)methyl)cyclopropanecarbonitrile

To a mixture of 3-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazole (300 mg),cesium carbonate (872 mg) and DMF (5 mL) was added dropwise1-(bromomethyl)cyclopropanecarbonitrile (205 mg) at 0° C., and themixture was stirred at 70° C. for 2 hr. The reaction mixture was pouredinto ice water at room temperature. The resulting solid was collected byfiltration, washed with water and dried under reduced pressure to givethe title compound (310 mg).

MS: [M+H]⁺ 360.1.

B)1-((3-(3,5-bis(trifluoromethyl)phenyl-1H-pyrazol-1-yl)methyl)cyclopropanecarboxylicacid

To a mixture of1-((3-(3,5-bis(trifluoromethyl)phenyl-1H-pyrazol-1-yl)methyl)cyclopropanecarbonitrile(310 mg) and acetic acid (5 mL) was added 6N hydrochloric acid (5 mL),and the mixture was heated under reflux for 24 hr. The reaction mixturewas concentrated under reduced pressure, water was added to the obtainedresidue, and the mixture was extracted with ethyl acetate. The extractwas washed with water and saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by HPLC (C18, mobile phase: water/acetonitrile (0.1% HCO₂Hcontaining system)) to give the title compound (180 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 1.07-1.16 (2H, m), 1.16-1.26 (2H, m), 4.41(2H, s), 7.07 (1H, d, J=2.4 Hz), 7.87 (1H, d, J=2.4 Hz), 8.00 (1H, s),8.40 (2H, s), 12.56 (1H, brs).

Reference Example 73-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-2-methylpropanoicacid

To a mixture of 3-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazole (500 mg),cesium carbonate (1.45 g) and DMF (10 mL) was added dropwise3-bromo-2-methylpropanoic acid (357 mg) at 0° C., and the mixture wasstirred at 70° C. for 2 hr. To the reaction mixture was added water, andthe mixture was extracted with ethyl acetate. The extract was washedwith water and saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by HPLC(C18, mobile phase: water/acetonitrile (0.1% containing system)) to givethe title compound (45 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 1.06 (3H, d, J=6.8 Hz), 2.94-3.08 (1H, m),4.23 (1H, dd, J=13.6, 6.8 Hz), 4.43 (1H, dd, J=13.6, 6.8 Hz), 7.07 (1H,d, J=2.0 Hz), 7.86 (1H, d, J=2.0 Hz), 8.01 (1H, s), 8.40 (2H, s), 12.53(1H, brs).

According to the methods shown in the above-mentioned Reference Examplesor a method analogous thereto, the Reference Example compounds in thefollowing Tables were produced. The Reference Example compounds areshown in the following Tables. In the Tables, MS shows measured values.

TABLE 2 Ref. Ex. No. IUPAC name structural formula salt MS 1 ethyl((4-(3,5- bis(trifluoromethyl)phenyl)- 1,3-oxazol-2- yl)sulfanyl)acetate

400.1 2 ((4-(3,5- bis(trifluoromethyl)phenyl)- 1,3-oxazol-2-yl)sulfanyl)acetic acid

369.9 3 ethyl ((6-(3,5 - bis(trifluoromethyl)phenyl)-pyridin-3-yl)sulfanyl)acetate

410.1 4 ((6-(3,5-bis(trifluoromethyl)- phenyl)pyridin-3-yl)sulfanyl)acetic acid

382.0 5 3-(3-(3,5- bis(trifluoromethyl)phenyl)- 1H-pyrazol-1-yl)butanoicacid

364.9 6 1-((3-(3,5-bis(trifluoro- methyl)phenyl)-1H-pyrazol-1-yl)methyl)cyclopropane- carboxylic acid

376.9 7 3-(3-(3,5- bis(trifluoromethyl)phenyl)- 1H-pyrazol-1-yl)-2-methylpropanoic acid

364.9

Experimental Example 1

Using the Retinol-RBP4-TTR ELISA system shown below, the action of thecompound of the present invention to inhibit the binding of RBP4 andretinol and TTR was evaluated.

1A: Cloning of Human RBP4 Gene and Human TTR Gene

Human RBP4 gene was cloned by PCR using human Universal cDNA (Clontech,QUICK-Clone cDNA) as a template, and the following primer sets.

RBPU: (SEQ ID NO: 1) 5′-ATATGGATCCACCATGAAGTGGGTGTGGGCGCTC-3′ RBPL:(SEQ ID NO: 2) 5′-ATATGCGGCCGCCTACAAAAGGTTTCTTTCTGATCTGC-3′

PCR reaction was performed according to the protocol attached toPyrobest polymerase (TAKARA BIO INC., LTD.). The obtained PCR productwas subjected to agarose gel (1%) electrophoresis, an about 0.6 kb DNAfragment containing RBP4 gene was recovered from the gel, digested withrestriction enzymes BamHI and NotI. DNA fragment after the restrictionenzyme treatment was subjected to agarose gel (1%) electrophoresis, anabout 0.6 kb DNA fragment was recovered, and ligated to plasmidpcDNA3.1(+) (Invitrogen) digested with restriction enzymes BamHI andNotI to give an expression plasmid pcDNA3.1(+)/hRBP4. The DNA sequenceof the inserted fragment was confirmed to have matched with the objectsequence.

Human TTR gene was cloned by PCR reaction using human small intestinecDNA (Clontech, QUICK-Clone cDNA) as a template, and the followingprimer sets.

TTRU: (SEQ ID NO: 3) 5′-ATATGGATCCACCATGGCTTCTCATCGTCTGCTCC-3′ TTRL:(SEQ ID NO: 4) 5′-ATATGCGGCCGCTCATTCCTTGGGATTGGTGACGA-3′

PCR reaction was performed according to the protocol attached toPyrobest polymerase (TAKARA BIO INC., LTD.). The obtained PCR productwas subjected to agarose gel (1%) electrophoresis, a 0.5 kb DNA fragmentcontaining TTR gene was recovered from the gel, digested withrestriction enzymes BamHI and NotI. DNA fragment after the restrictionenzyme treatment was subjected to agarose gel (1%) electrophoresis, anabout 0.5 kb DNA fragment was recovered, and ligated to plasmidpcDNA3.1(+) (Invitrogen) digested with restriction enzymes BamHI andNotI to give an expression plasmid pcDNA3.1(+)/hTTR. The DNA sequence ofthe inserted fragment was confirmed to have matched with the objectsequence.

1B: Construction of Human RBP4-his Expression Plasmid

EcoRI site was introduced into the 3′-end of hRBP4 gene by PCR using theexpression plasmid pcDNA3.1(+)/hRBP4 prepared in the above-mentioned 1Aas a template and the following primer sets.

CMVP: (SEQ ID NO: 5) 5′-TGGGAGGTCTATATAAGCAGAGCTCG-3′ RBPECO:(SEQ ID NO: 6) 5′-ATATGAATTCTTCCTTGGGATTGGTGAC-3′

PCR was performed according to the protocol attached to Z-Taq polymerase(TAKARA BIO INC., LTD.). The obtained PCR product was purified byQIAquick PCR purification Kit (QIAGEN), and digested with restrictionenzymes BamHI and EcoRI. DNA fragment after the restriction enzymetreatment was subjected to agarose gel (1%) electrophoresis, theobtained about 0.6 kb DNA fragment was recovered, and ligated to plasmidpcDNA3.1(+) (Invitrogen) digested with restriction enzymes BamHI andEcoRI to give pcDNA3.1(+)/hRBP4-Eco having EcoRI site at the 3′-end ofhRBP4 gene.

EcoRI site was introduced into the 3′-end of hTTR gene by PCR using theexpression plasmid pcDNA3.1(+)/hTTR prepared in the above-mentioned 1Aas a template and CMVP and TTRECO primer sets.

TTRECO: (SEQ ID NO: 7) 5′-ATATGAATTCCAAAAGGTTTCTTTCTGATC-3′

PCR reaction was performed according to the protocol attached to Z-Taqpolymerase (TAKARA BIO INC., LTD.). The obtained PCR product waspurified by QIAquick PCR purification Kit (QIAGEN), and digested withrestriction enzymes BamHI and EcoRI. DNA fragment after the restrictionenzyme treatment was subjected to agarose gel (1%) electrophoresis, theobtained about 0.6 kb DNA fragment was recovered, and ligated to plasmidpcDNA3.1(+) (Invitrogen) digested with restriction enzymes BamHI andEcoRI to give pcDNA3.1(+)/hTTR-Eco having EcoRI site at the 3′-end ofhTTR gene.

TTR-His expression plasmid pcDNA3.1(+)/hTTR-His wherein His tag is addedto the C-terminal of human TTR was prepared by inserting a synthetic DNAfragment containing His tag sequence prepared by annealing the followingoligoDNA into the EcoRI site and NotI site of pcDNA3.1(+)/hTTR-Ecoprepared as mentioned above.

HISENU: (SEQ ID NO: 8) 5′-AATTCCATCATCATCATCATCACTAGGC-3′ HISENL:(SEQ ID NO: 9) 5′-GGCCGCCTAGTGATGATGATGATGATGG-3′

HISENU and HISENL were each dissolved at a concentration of 25 pmole/uL,heated at 94° C. for 5 min, cooled to room temperature to allow forannealing, whereby synthetic DNA fragment containing His tag sequencewas obtained. pcDNA3.1(+)/hTTR-Eco was digested with EcoRI and NotI, theDNA fragment after the restriction enzyme treatment was subjected toagarose gel (1%) electrophoresis, the obtained about 5.9 kb DNA fragmentwas recovered, and a synthetic DNA fragment containing His tag sequencewas ligated thereto to give TTR-His expression plasmidpcDNA3.1(+)/hTTR-His wherein His tag is added to the C-terminal of humanTTR.

RBP4-His expression plasmid pcDNA3.1(+)/hRBP4-His wherein His tag isadded to the C-terminal of human RBP4 was prepared as follows.pcDNA3.1(+)/hRBP4-Eco was digested with restriction enzymes EcoRI andDraIII, subjected to agarose gel (1%) electrophoresis, and the obtainedabout 6.0 kb DNA fragment was recovered. pcDNA3.1(+)/hTTR-His wasdigested with restriction enzymes EcoRI and DraIII, subjected to agarosegel (1%) electrophoresis, and the obtained about 6.0 kb DNA fragment wasrecovered. The both fragments were ligated to give RBP4-His expressionplasmid pcDNA3.1(+)/hRBP4-His wherein His tag is added to the C-terminalof human RBP4.

1C: Preparation of Human RBP4-his

Human RBP4-His was expressed using FreeStyle 293 expression system(Invitrogen) and expression plasmid pcDNA3.1(+)/hRBP4-His prepared inthe above-mentioned 1B. According to the protocol attached to theFreeStyle 293 expression system, 600 mL of culture medium was used forexpression. After transfection and 3 days of culture, the culturesupernatant containing secreted hRBP4-His was recovered. The culturesupernatant was repeatedly concentrated using VIVACELL 250 (molecularweight cutoff 10K, VIVASCIENCE), and diluted with 20 mM Tris (pH 8),whereby the buffer was substituted. The liquid was adsorbed by passagethrough TOYOPEARL DEAE-650 M column (1 cm IDx10 cm, Tosoh Corporation)equilibrated with 20 mM Tris buffer (pH 8) at a flow rate of 2.5 mL/min,and eluted at 0 to 0.35 M NaCl gradient to give human RBP4-Hisfractions. These fractions were concentrated to about 5 mL usingVivaspin 20 (molecular weight cutoff 10K, VIVASCIENCE). The Concentratedsolution was passed through HiLoad 26/60 Superdex 200 pg column (2.6 cmIDx60 cm, GE Healthcare) equilibrated with TBS (pH 7.4), and eluted withTBS (pH 7.4). The fraction containing human RBP4-His was recovered, andconcentrated to about 8 mL using Vivaspin 20 (molecular weight cutoff10K, VIVASCIENCE). About 8 mg of human RBP4-His was obtained from 600 mLof the culture medium.

1D: Preparation of Human TTR

Human TTR was expressed using FreeStyle 293 expression system(Invitrogen) and expression plasmid pcDNA3.1(+)/hTTR prepared in theabove-mentioned 1A. According to the protocol attached to the FreeStyle293 expression system, 600 mL of culture medium was used for expression.After transfection and 3 days of culture, the culture supernatantcontaining secreted human TTR was recovered. The culture supernatant wasrepeatedly concentrated using VIVACELL 250 (molecular weight cutoff 10K,VIVASCIENCE), and diluted with 20 mM Tris (pH 8), whereby the buffer wassubstituted. The liquid was adsorbed by passage through TOYOPEARLDEAE-650 M column (1 cm IDxl0 cm, Tosoh Corporation) equilibrated with20 mM Tris buffer (pH 8) at a flow rate of 2.5 mL/min, and eluted at 0to 0.55 M NaCl gradient to give human TTR fractions. These fractionswere repeatedly concentrated using Vivaspin 20 (molecular weight cutoff10K, VIVASCIENCE), and diluted with 20 mM Tris (pH 8), whereby thebuffer was substituted. The liquid was adsorbed by passage throughHiLoad Q Sepharose HP column (1.6 cm IDxl0 cm, GE Healthcare)equilibrated with 20 mM Tris buffer (pH 8) at a flow rate of 1.0 mL/min,and eluted at 0 to 0.4 M NaCl gradient to give human TTR fractions.These fractions were concentrated to about 5 mL using Vivaspin 20(molecular weight cutoff 10K, VIVASCIENCE). The Concentrated solutionwas passed through HiLoad 26/60 Superdex 75 pg column (2.6 cm ID×60 cm,GE Healthcare) equilibrated with PBS (pH 7.4), and eluted with TBS (pH7.4). The fraction containing human TTR was recovered, and concentratedto about 5 mL using Vivaspin 20 (molecular weight cutoff 10K,VIVASCIENCE). About 6 mg of human TTR was obtained from 600 mL of theculture medium.

1E: Preparation of Human TTR-Biotin

Human TTR prepared in the above-mentioned 1D was labeled with biotinusing Biotinylation Kit (Sulfo-Osu) (DOJINDO LABORATORIES) according tothe attached protocol to prepare human TTR-biotin. Human TTR (5.0 mg)was repeatedly concentrated using Vivaspin 6 (molecular weight cutoff10K, VIVASCIENCE) and diluted with 50 mM NaHCO3, whereby the buffer wassubstituted. This solution was diluted with 50 mM NaHCO₃ to set theconcentration of human TTR to 2.0 mg/mL, and aqueous Biotin-(AC5)2Sulfo-OSu solution (10 mg/mL) (9.9 uL) was added and the mixture wasreacted at 25° C. for 2 hr. The solution after the reaction was passedthrough NAP-25 column (GE Healthcare) equilibrated with PBS (pH 7.4),eluted with PBS (pH 7.4) and an eluate (3.5 mL) containing humanTTR-biotin was recovered.

1F: Binding Assay by Retinol-RBP4-TTR ELISA

This ELISA system detects a complex with RBP4 and TTR based on theretinol dependent binding of RBP4 to TTR.

The His-tagged human RBP4 used was prepared in the above-mentioned 1C.

The biotinylated human TTR used was prepared in the above-mentioned 1E.

Streptavidin (20 μl) (10 μg/ml Streptavidin type II (Wako Pure ChemicalIndustries, Ltd.), 10 mM Tris-HCl (pH 7.5), 10 mM NaCl) was added to a384 well blackplate (Nunc MaxiSorp, Thermo Fisher Scientific Inc.), andthe plate was centrifuged (1000 rpm, 1 min) and coated at 4° C.overnight. The plate was washed twice with PBST (PBS, 0.05% Tween 20,100 μl/well), and blocked with 25% Block Ace (Snow Brand Milk ProductsCo., Ltd., PBS, 100 μl/well). The plate was subjected to centrifugation(1000 rpm, 1 min), and incubated at room temperature for 4 hr or 4° C.overnight. The plate was washed twice with PBST (PBS, 0.05% Tween 20,100 μl/well), and biotinylated human TTR (stock solution concentration1.0 mg/ml) diluted 750-fold with PBST was added at 20 μl/well. The platewas subjected to centrifugation (1000 rpm, 1 min), and further stood atroom temperature for 1.5 hr or 4° C. overnight. The plate was washed 3times with PBST (100 μl/well), and His-tagged human RBP4 (stock solutionconcentration 1.28 mg/ml) diluted 4000-fold with a reaction buffer (50mM Tris-HCl, 150 mM NaCl, 0.005% Tween 20, 1 mM DTT, 0.1% BSA) was addedat 10 μl/well. The dilution of the compound (200-fold concentration) wasprepared with DMSO, and 1.6 μl each was added to a reaction buffer (320μl) containing retinol (50 nM) (Sigma-Aldrich Co.). A reaction buffer(320 μl) containing retinol and added with DMSO was used as a positivecontrol, and a reaction buffer (320 μl) not containing retinol and addedwith DMSO was used as a negative control. A mixed solution of retinoland the compound was added to the plate at 15 μl/well. The plate wasstirred in a plate mixer, centrifuged (1000 rpm, 1 min), and reacted atroom temperature for 2 hr. Anti-His HRP-conjugated antibody (QIAGEN)solution diluted with a reaction buffer was added at 10 μl/well,centrifuged (1000 rpm, 1 min), and reacted at room temperature for 30min. The plate was washed 3 times with PBST (100 μl/well), SuperSignalELISA Femto Maximum Sensitivity Substrate reagent (PIERCE, Thermo FisherSceintific Inc.) was added at 30 μl/well, and the luminescence wasmeasured by a plate reader (Envision).

The binding inhibitory activity of the compound was determined by100×(positive control value−test compound value)/(positive controlvalue−negative control value). The results are shown in Table 3.

TABLE 3 Example human RBP4 binding inhibitory No. activity (% at 10 μM)Example 1 98 Example 2 99 Example 3 100 Example 4 100 Example 5 100

From the above-mentioned results, it was clarified that the compound ofthe present invention inhibits the binding of RBP4, and retinol and TTR.

Experimental Example 2

The blood RBP4-lowering action of the compound of the present inventionwas evaluated using C57BL/6J mouse.

Male 7- to 10-week-old C57BL/6J mice (Japan Charles River) wereacclimation reared under free food ingestion conditions on CE-2 solidfeed (CLEA Japan, Inc.) for 4 to 6 days, and randomly grouped (4 or 5per group). On the day of the test, blood samples were collected fromthe tail vein, and plasma was separated (0 hr value). Thereafter, a testcompound (Example 1, 2, 3, 4, 5, 6, 7 or 8) was orally administered at adose of 3 mg/kg or 10 mg/kg (solvent: 0.5% methylcellulose solution (10mL/kg)). At 8 and 24 hr after the compound was administered, bloodsamples were collected from the tail vein and plasma was separated. A0.5% methylcellulose solution (10 mL/kg) was orally administered to thecontrol group.

The amount of RBP4 in the collected plasma was measured by the ELISAmethod. Using rabbit anti-mouse RBP4 polyclonal antibody (Hokudo Co.,Ltd.), RBP4 was quantified by the following process. A 96 well ELISAplate was coated with 50 μg/mL antibody (100 μL), and stood at 4° C.overnight or at room temperature for 2 hr. After blocking with BlockAce(Dainippon Pharmaceutical Co., Ltd.), 100 μL of mouse RBP4 or sample wasadded and the plate was stood at room temperature for 2 hr, washed withPBS-0.5% Tween20, added with HRP-labeled anti-RBP4 antibody (prepared bylabeling RBP4 polyclonal antibody (Hokudo Co., Ltd.) with HRP (DOJINDOLABORATORIES)) (100 μL), and stood at room temperature for 1 hr. Afterwashing, TMB (Sigma) was added at room temperature for 20 min to allowfor color development. The reaction was quenched with 2N sulfuric acidand the absorbance at A450 nm was measured by a platereader. Variationfrom the initial value of each individual was taken as the relativevalue to the control group (initial value/control value, %) at each timepoint. The results are shown below in mean±standard deviation (n=4 or5).

TABLE 4 RBP4 (initial value/ Example control value %) No. dose 8 hrlater 24 hr later 1 10 mg/kg 37.25 ± 11.45 61.81 ± 14.79 2 10 mg/kg23.93 ± 5.84  64.87 ± 16.79 3 10 mg/kg 20.70 ± 1.55  49.64 ± 10.48 4  3mg/kg 19.86 ± 11.85 54.29 ± 19.15 5  3 mg/kg 32.14 ± 6.82  36.20 ± 1.87 6 10 mg/kg 58.17 ± 8.61  79.70 ± 5.22  7 10 mg/kg 43.66 ± 4.92  71.75 ±8.77 

All the above-mentioned compounds showed a lower value, by single oraladministration, than the control group 8 hr after the administration.These results show that the compound of the present invention has ablood RBP4-lowering action.

Experimental Example 3

The suppressive action for accumulation of retinoid metabolitebis-retinoid N-retinylidene-N-retinylethanolamine (A2E) in the eyeball,of the compound of the present invention, was evaluated usingATP-binding cassette A4 knockout (ABCA4 KO) mouse. A2E is the majorconstituent component of Lipofuscin in the eyeball, and is involved inthe onset and pathology progression in atrophic age-related maculardegeneration and Stargardt's disease. ABCA4 KO mouse was confirmed toshow remarkable accumulation of A2E, Lipofuscin along with aging, and isknown as an animal model of atrophic age-related macular degenerationand Stargardt's disease.

8-Week-old male ABCA4 KO mice were randomly grouped, and 0.5%methylcellulose solution was orally administered to the control group,and 0.5% methylcellulose suspension of a compound at a dose shown in thefollowing Table was orally administered to the test compound group, eachonce per day at 10 mL/kg. Each group contained 6 or 7 mice. Afterrepetitive administration for 8 or 12 weeks, eyeball was isolated underanesthesia.

In the eyeball, A2E was measured by the HPLC method. A2E referencestandard was synthesized from all-trans retinal, ethanolamine in aceticacid-added ethanol. First, 0.3 mL of PBS and zirconia beads were addedto the eyeball, and homogenate was prepared using Mixer Mill MM 300(QIAGEN). A chloroform:methanol (2:1) solution (0.8 mL) was added andthe mixture was stirred for 5 min. The lower layer was separately takenin a different tube, the chloroform:methanol (2:1) solution (0.6 mL) wasfurther added and the mixture was stirred for 5 min. The lower layer wascombined with one separated earlier, and dried to solidness by blowingnitrogen gas. 0.05 mL of 85% acetonitrile solution was added and themixture was stirred to give a measurement sample. For HPLC, Alliancee2695 and Photo diode array 2998 (PDA) (Waters) were used, and Empower 2was used as an analysis software. The column used was Atlantis dC18 (3μm, 3.9×150 mm) (Waters), and the column temperature was set to 40° C.As the mobile phase, a mixed solution of acetonitrile and distilledwater (containing 0.1% trifluoroacetic acid) was used at 1 mL/min and,as the gradient conditions, acetonitrile concentration was raised from85% to 100% over 15 min, and then immediately decreased to 85% and onesample was monitored for 20 min. Quantification was performed atultraviolet absorbance at 440 nm by PDA.

TABLE 5 Example No. dose A2E (% of control value) 2 10 mg/kg 77.63 ±9.06  3 10 mg/kg 73.90 ± 15.58 4  1 mg/kg 79.47 ± 14.53 5  3 mg/kg 59.10± 10.33

Repetitive administration of all the above-mentioned compoundssuppressed accumulation of retinoid metabolite A2E in the eyeball ofABCA4 KO mouse.

Formulation Example 1 (Production of Capsule)

1) compound of Example 1 30 mg 2) microcrystalline cellulose 10 mg 3)lactose 19 mg 4) magnesium stearate  1 mg total 60 mg

1), 2), 3) and 4) are mixed and filled in a gelatin capsule.

Formulation Example 2 (Production of Tablet)

1) compound of Example 1 30 g 2) lactose 50 g 3) cornstarch 15 g 4)calcium carboxymethylcellulose 44 g 5) magnesium stearate 1 g 1000tablets 140 g in total

The total amount of 1), 2), 3) and 30 g of 4) are kneaded with water,vacuum dried and sieved. The sieved powder is mixed with 14 g of 4) and1 g of 5), and the mixture is punched by a tableting machine. In thisway, 1000 tablets containing 30 mg of the compound of Example 1 pertablet are obtained.

Formulation Example 3 (Production of Ointment)

1) compound of Example 1 0.5 g 2) liquid paraffin 1 g 3) whitepetrolatum 98.5 g total 100 g

1), 2) are thoroughly mixed in a mortar, 3) is gradually added withkneading to the total amount of 100 g. The obtained mixture is dividedand filled in a tube to give an ointment.

Formulation Example 4 (Production of Eye Drop)

 1) compound of Example 1 0.05 g  2) boric acid 1.2 g  3) L-sodiumglutamate 0.2 g  4) sodium edetate 0.005 g  5) dibutylhydroxytoluene0.005 g  6) chlorobutanol 0.1 g  7) benzalkonium chloride (10 w/v %)0.05 mL  8) l-menthol 0.008 g  9) macrogol 4000 0.4 g 10) sodiumhydroxide q.s. 11) sterile purified water added to 100 mL

The above-mentioned components are mixed to give an eye drop.

INDUSTRIAL APPLICABILITY

The compound of the present invention has a superior RBP4-loweringaction, and is useful as a medicament for the prophylaxis or treatmentof a disease or condition mediated by an increase in RBP4 or retinolsupplied by RBP4 such as age-related macular degeneration, Stargardt'sdisease and the like.

This application is based on patent application No. 2014-217770 filed inJapan, the contents of which are incorporated in full herein by thisreference.

SEQ ID NO: 1: PCR primer (RBPU)SEQ ID NO: 2: PCR primer (RBPL)SEQ ID NO: 3: PCR primer (TTRU)SEQ ID NO: 4: PCR primer (TTRL)SEQ ID NO: 5: PCR primer (CMVP)SEQ ID NO: 6: PCR primer (RBPECO)SEQ ID NO: 7: PCR primer (TTRECO)SEQ ID NO: 8: oligonucleotide (HISENU) for producing synthetic genesegment containing His tag sequenceSEQ ID NO: 9: oligonucleotide (HISENL) for producing synthetic genesegment containing His tag sequence

1. A compound represented by the formula (I):

wherein ring A is an optionally further substituted monocyclicnitrogen-containing aromatic heterocycle; X is CH₂ or O; and R is ahydrogen atom or a C₁₋₆ alkyl group, excluding3-{4-[3,5-bis(trifluoromethyl)phenyl]-1,3-oxazol-2-yl}propanoic acid;3-{4-[3,5-bis(trifluoromethyl)phenyl]-1,3-oxazol-2-yl}propanoic acidmethyl ester;3-{4-[3,5-bis(trifluoromethyl)phenyl]-1,3-oxazol-2-yl}propanoic acidethyl ester; and3-(3-(3,5-bis(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)propanoicacid, or a salt thereof.
 2. The compound according to claim 1, wherein Ris a hydrogen atom, or a salt thereof.
 3. The compound according toclaim 1, wherein ring A is an optionally further substituted, monocyclicnitrogen-containing aromatic heterocycle free of a hetero atom otherthan nitrogen atom as a ring-constituting atom, or a salt thereof. 4.The compound according to claim 1, wherein ring A is a pyrazole ring, apyridine ring or a pyrimidine ring, or a salt thereof. 5.((2-(3,5-bis(Trifluoromethyl)phenyl)pyrimidin-5-yl)oxy)acetic acid or asalt thereof. 6.((6-(3,5-bis(Trifluoromethyl)phenyl)pyridin-3-yl)oxy)acetic acid or asalt thereof. 7.3-(3-(3,5-bis(Trifluoromethyl)phenyl)-1H-pyrazol-1-yl)propanoic acid ora salt thereof. 8.((4-(3,5-bis(Trifluoromethyl)phenyl)-1,3-oxazol-2-yl)oxy)acetic acid ora salt thereof. 9.((1-(3,5-bis(Trifluoromethyl)phenyl)-1H-pyrazol-3-yl)oxy)acetic acid ora salt thereof.
 10. A medicament comprising the compound according toclaim 1 or a salt thereof. 11-13. (canceled)
 14. A method of loweringretinol binding protein 4 in a mammal, comprising administering aneffective amount of the compound according to claim 1, or a salt thereofto the mammal.
 15. A method for the prophylaxis or treatment of maculardegeneration and/or Stargardt's disease in a mammal, comprisingadministering an effective amount of the compound according to claim 1,or a salt thereof to the mammal.
 16. (canceled)
 17. The compoundaccording to claim 2, wherein ring A is an optionally furthersubstituted, monocyclic nitrogen-containing aromatic heterocycle free ofa hetero atom other than nitrogen atom as a ring-constituting atom, or asalt thereof.
 18. The compound according to claim 2, wherein ring A is apyrazole ring, a pyridine ring or a pyrimidine ring, or a salt thereof.19. A medicament comprising the compound according to claim 2 or a saltthereof.
 20. A method of lowering retinol binding protein 4 in a mammal,comprising administering an effective amount of the compound accordingto claim 2, or a salt thereof to the mammal.
 21. A method for theprophylaxis or treatment of macular degeneration and/or Stargardt'sdisease in a mammal, comprising administering an effective amount of thecompound according to claim 2, or a salt thereof to the mammal.